Compounds for the treatment of neurodegenerative disorders

ABSTRACT

The present invention relates to compounds of the Formula  
                 
 
wherein R 3 , R 5 , R 7 , U, X, Y and Z are as defined. Compounds of the Formula I have activity inhibiting production of Aβ-peptide. This invention also relates to pharmaceutical compositions and methods of treating diseases, for example, neurodegenerative diseases, e.g., Alzheimer&#39;s disease, in a mammal comprising compounds of the Formula I.

CROSS REFERENCE TO RELATED APPLICATION

This Application claims priority from U.S. Provisional Application No.60/496,735, filed Aug. 21, 2003.

FIELD OF THE INVENTION

The present invention relates to the treatment of Alzheimer's diseaseand other neurodegenerative and/or neurological disorders in mammals,including humans. This invention also relates to inhibiting, in mammals,including humans, the production of Aβ-peptides that can contribute tothe formation of neurological deposits of amyloid protein. Moreparticularly, this invention relates to oxazole compounds useful for thetreatment of neurodegenerative and/or neurological disorders, such asAlzheimer's disease and Down's Syndrome, related to Aβ-peptideproduction.

BACKGROUND OF THE INVENTION

Dementia results from a wide variety of distinctive pathologicalprocesses. The most common pathological processes causing dementia areAlzheimer's disease (AD), cerebral amyloid angiopathy (CAA) andprion-mediated diseases (see, e.g., Haan et al. Clin. NeuroL Neurosurg.1990, 92(4):305-310; Glenner et al. J Neurol. Sci. 1989, 94:1-28). ADaffects nearly half of all people past the age of 85, the most rapidlygrowing portion of the United States population. As such, the number ofAD patients in the United States is expected to increase from about 4million to about 14 million by the middle of the next century.

Treatment of AD typically is the support provided by a family member inattendance. Stimulated memory exercises on a regular basis have beenshown to slow, but not stop, memory loss. A few drugs, for exampleAricep™, provide treatment of AD.

A hallmark of AD is the accumulation in the brain of extracellularinsoluble deposits called amyloid plaques and abnormal lesions withinneuronal cells called neurofibrillary tangles. Increased plaqueformation is associated with an increased risk of AD. Indeed, thepresence of amyloid plaques, together with neurofibrillary tangles, arethe basis for definitive pathological diagnosis of AD.

The major components of amyloid plaques are the amyloid Aβ-peptides,also called Aβ-peptides, which consist of three proteins having 40, 42or 43 amino acids, designated as the Aβ₁₋₄₀ Aβ₁₋₄₂ and Aβ₁₋₄₃ peptides,respectively. The Aβ-peptides are thought to cause nerve celldestruction, in part, because they are toxic to neurons in vitro and invivo.

The Aβ peptides are derived from larger amyloid precursor proteins (APPproteins), which consist of four proteins containing 695, 714, 751 or771 amino acids, designated as the APP₆₉₅, APP₇₁₄, APP₇₅, and APP₇₇₁,respectively. Proteases are believed to produce the Aβ peptides bycleaving specific amino acid sequences within the various APP proteins.The proteases are named “secretases” because the Aβ-peptides theyproduce are secreted by cells into the extracellular environment. Thesesecretases are each named according to the cleavage(s) they make toproduce the Aβ-peptides. The secretase that forms the amino terminal endof the Aβ-peptides is called the beta-secretase. The secretase thatforms the carboxyl terminal end of the Aβ-peptides is called thegamma-secretase (Haass, C. and Selkoe, D. J. 1993 Cell 75:1039-1042).

This invention relates to novel compounds that inhibit Aβ-peptideproduction, to pharmaceutical compositions comprising such compounds,and to methods of using such compounds to treat neuorodegenerativeand/or neurological disorders.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula I

The ring containing X, Y, U is an aromatic ring in which one of the X,Y, U is a S and the other two of the X, Y, U are N as shown below I-A toI-C.

wherein Z is selected from —C(═O)CHR¹R², —C(═S)CHR¹R², —(C═NR⁸)CHR¹R²,—C(═O)C(═O)R¹ and —S(O)₂—R¹;

-   -   R¹ is selected from —C₁-C₂₀ alkyl, —C₂-C₂₀ alkenyl, —C₂-C₂₀        alkynyl, —C₁-C₂₀ alkoxy, —C₂-C₂₀ alkenoxy, —C₂-C₂₀ alkynoxy,        —C₃-C₂₀ cycloalkyl, —C₄-C₂₀ cycloalkenyl, (C₁₀-C₂₀)bi- or        tricycloalkyl, (C₁₀-C₂₀)bi- or tricycloalkenyl, (4-20 membered)        heterocycloalkyl, —C₆-C₂₀ aryl and (5-20 membered) heteroaryl;    -   wherein R¹ is optionally independently substituted with from one        to six fluorine atoms or with from one to three substituents        independently selected from the group R^(1a);    -   R^(1a) is in each instance independently selected from —OH,        —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —C₁-C₆ alkoxy,        —C₂-C₆ alkenoxy, —C₂-C₆ alkynoxy, —CF₃, —OCF₃, —Cl, —Br, —I,        —CN, —NO₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —SO₂—NR⁹R¹⁰, —C(═O)R¹¹,        —S(O)_(n)—R¹¹, —C(═O)OR¹², —C₃-C₁₅ cycloalkyl, —C₄-C₁₅        cycloalkenyl, —(C₅-C₁₁)bi- or tricycloalkyl, —(C₇-C₁₁)bi- or        tricycloalkenyl, -(4-20 membered) heterocycloalkyl, —C₆-C₁₅        aryl, -(5-15 membered) heteroaryl, —C₆-C₁₅ aryloxy and -(5-15        membered) heteroaryloxy, wherein said cycloalkyl, cycloalkenyl,        bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl,        aryl, heteroaryl, aryloxy and heteroaryloxy are each optionally        independently substituted with from one to three substituents        independently selected from the group R^(1b);    -   R^(1b) is in each instance independently selected from —OH,        —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkoxy,        —C₂-C₆ alkenoxy, —C₂-C₆ alkynoxy, —C₁-C₆ hydroxyalkyl, —F, —Cl,        —Br, —I, —CN, —NO₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹,        —S(O)_(n)—R¹¹, —C₆-C₁₅ aryloxy and -(5-15 membered)        heteroaryloxy, wherein said alkyl, alkenyl and alkynyl are each        optionally independently substituted with from one to six        fluorine atoms or with from one to two substituents        independently selected from —C₁-C₄ alkoxy, or with a hydroxy        group;    -   R⁹ and R¹⁰ are in each instance each independently selected from        —H, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —CF₃,        —C(═O)R¹¹, —S(O)_(n)—R¹¹, —C(═O)OR¹², —C(═O)NR¹¹R¹²,        —SO₂—NR¹¹R¹², —(C_(zero)-C₄ alkylene)-(C₃-C₂₀ cycloalkyl),        —(C_(zero)-C₄ alkylene)-(C₄-C₈ cycloalkenyl), —(C_(zero)-C₄        alkylene)-((C₅-C₁₁)bi- or tricycloalkyl), —(C_(zero)-C₄        alkylene)-((C₇-C₁₁)bi- or tricycloalkenyl), —(C_(zero)-C₄        alkylene)-((5-10 membered) heterocycloalkyl), (C_(zero)-C₄        alkylene)-(C₆-C₁₀ aryl) and —(C_(zero)-C₄ alkylene)-((5-10        membered) heteroaryl), wherein said aryl, heteroaryl, alkyl,        alkenyl and alkynyl are each optionally independently        substituted with from one to six fluorine atoms or with from one        to two substitutents independently selected from —C₁-C₄ alkoxy,        or with a hydroxy group, and wherein said cycloalkyl,        cycloalkenyl, bi-or tricycloalkyl, bi- or tricycloalkenyl,        heterocycloalkyl, aryl and heteroaryl are each optionally        independently substituted with from one to three substituents        independently selected from —OH, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl,        —C₂-C₁₂ alkynyl, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆        alkynoxy, —C₁-C₆ hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂,        —CF₃, —NH₂, —C(═O)NH₂, —SO₂—NR⁹R¹⁰, —C(═O)H and —C(═O)OH,        wherein said alkyl, alkenyl and alkynyl substituents are each        optionally independently further substituted with from one to        six fluorine atoms or with from one to two substituents        independently selected from —C₁-C₄ alkoxy, or with a hydroxy        group;    -   or NR⁹R¹⁰ may in each instance independently optionally form a        heterocycloalkyl moiety of from four to ten ring members, said        heterocycloalkyl moiety optionally containing one to two further        heteroatoms independently selected from N, O and S, and        optionally containing from one to three double bonds, wherein        the carbon atoms of the heterocycloalkyl moiety of NR⁹R¹⁰ are        optionally independently substituted with from one to three        substituents independently selected from —OH, —C₁-C₁₂ alkyl,        —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —C₁-C₆ alkoxy, —C₂-C₆        alkenoxy, —C₂-C₆ alkynoxy, —F, —Cl, —Br, —I, —CF₃, —NH₂,        —C(═O)NH₂, —SO₂—NH₂, —C(═O)R¹¹, —S(O)_(n)—R¹¹, (C_(zero)-C₄        alkylene)-(C₆-C₁₀ aryl), (C_(zero)-C₄ alkylene)-((5-10 membered        heteroaryl), (C_(zero)-C₄ alkylene)-(C₆-C₁₀ cycloalkyl) and        (C_(zero)-C₄ alkylene)-((5-10 membered) heterocycloakyl, and        wherein the (C_(zero)-C₄ alkylene)-((5-10 membered)        heterocycloalkyl) substituent and the nitrogen atoms of said        heterocycloalkyl moiety of NR⁹R¹⁰ are each optionally        independently substituted with one substituent independently        selected from —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl,        —C(═O)NH₂, —SO₂—NH₂, C(═O)R¹¹, —S(O)_(n)—R¹¹, (C_(zero)-C₄        alkylene)-(C₆-C₁₀ aryl), (C_(zero)-C₄ alkylene)-((5-1 0        membered) heteroaryl), (C_(zero)-C₄ alkylene)-(C₆-C₁₀        cycloalkyl) and (C_(zero)-C₄ alkylene)-((5-10 membered)        heterocycloalkyl), and wherein said alkyl, alkenyl and alkynyl        substituents are each optionally independently further        substituted with from one to six fluorine atoms, or with from        one to two substituents independently selected from —C₁-C₄        alkoxy, or with a hydroxy group;    -   R¹¹ and R¹² are in each instance each independently selected        from —C₁-C₁₅ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,        —(C_(zero)-C₄ alkylene)-(C₃-C₁₅ cycloalkyl), —(C_(zero)-C₄        alkylene)-(C₄-C₈ cycloalkenyl), —(C_(zero)-C₄        alkylene)-((C₅-C₁₁)bi- or tricycloalkyl), —(C_(zero)-C₄        alkylene)-((C₇-C₁₁ )bi- or tricycloalkenyl), —(C_(zero)-C₄        alkylene)-(C₆-C₁₅ aryl), —(C_(zero)-C₄ alkylene)-((5-15        membered) heterocycloalkyl) and —(C_(zero)-C₄ alkylene)-((5-15        membered) heteroaryl);    -   wherein R¹¹ and R¹² are each optionally independently        substituted with from one to three substituents independently        selected from the group R^(1b);    -   R² is selected from —H, —OH, —NH₂, —CH₂OH, —OC(═O)CH₃,        —C(CH₃)₂OH, —C(CH₃)(CH₂CH₃)(OH), —C(OH)(C_(zero)-C₄        alkyl)(C_(zero)-C₄ alkyl), —OC(═O)R⁴ and —C(═O)OR⁴, wherein said        —OC(═O)R⁴ and —OC(═O)OR⁴ may optionally be a prodrug of the        corresponding OH of R²;    -   R³ is selected from —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl        and —(C_(zero)-C₄ alkylene)-(C₃-C₆ cycloalkyl), wherein when R³        is alkyl, alkenyl or alkynyl, R³ is optionally independently        substituted with a substituent independently selected from        —C₁-C₄ alkoxy, —OH, —F and —S(C₁-C₄ alkyl);    -   R⁴ is selected from —C₁-C₄ alkyl, —CH(OH)(C₁-C₄ alkyl),        -CH(OH)(C₅-C₆ aryl), —CH(OH)((5-6 membered) heteroaryl),        -CH(OH)(C₅-C₆ cycloalkyl), —CH(OH)((5-6 membered)        heterocycloalkyl);    -   R⁵ is selected from —H, —C₁-C₄ alkyl, —C₂-C₄ alkenyl, —C₂-C₄        alkynyl, —C(═O)(C₁-C₄alkyl), —C₆-C₁₀ aryl, -(5-20 membered)        heteroaryl, —SO₂—(C₆-C₁₀ aryl), —SO₂-((5-20 membered)        heteroaryl), —SO₂—CH₂—(C₆-C₂₀ aryl) and —SO₂—CH₂-((5-20        membered) heteroaryl);    -   R⁷ is selected from —H, —C₁-C₂₀ alkyl, —C₂-C₂₀ alkenyl, —C₂-C₂₀        alkynyl, —C₁-C₂₀ alkoxy, —C₂-C₂₀ alkenoxy, —C₂-C₂₀ alkynoxy, —F,        —Cl, —Br, —I, —CN, —NO₂, —OH, —CF₃, —NR⁹R¹⁰, —(C₁-C₁₁        alkylene)-NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —CHO, —S(O)_(n)—R¹¹,        —C(═O)OR¹², —(C_(zero)-C₄ alkylene)-(C₃-C₂₀ cycloalkyl),        —(C_(zero)-C₄ alkylene)-(C₄-C₂₀ cycloalkenyl), —(C_(zero)-C₄        alkylene)-((C₁₀-C₂₀)bi- or tricycloalkyl), —(C_(zero)-C₄        alkylene)-((C₁₀-C₂₀)bi- or tricycloalkenyl), —(C_(zero)-C₄        alkylene)-((3-20 membered) heterocycloalkyl), —(C_(zero)-C₄        alkylene)-(C₆-C₁₅ aryl), —(C_(zero)-C₁₁ alkylene)-(C(═O)R¹¹,        —C₁-C₁₁ alkylene)-(COOH), —(C_(zero)-C₁₁ alkylene)-CHO,        —SO₂NR⁹R¹⁰, —S—(C₁-C₂₀alkylene)(C═O)OR⁸,        —S—(C₁-C₂₀alkylene)-O-(C₁-C₁₁alkyl),        —S—(C₁-C₂₀alkylene)-O-(C₅-C₁₁aryl), —SO₂NR⁹R¹⁰,        —S—(C₁-C₂₀alkylene)-NR⁹R¹⁰, —(C₁-C₁₁        alkylene)-O-(C_(zero)-C₄alkylene)-O-(C₆-C₁₁aryl), and        —(C_(zero)-C₄ alkylene)-((5-15 membered) heteroaryl), wherein        said heterocycloalkyl optionally contains from one to four        double or triple bonds;    -   wherein R⁷ is optionally substituted with from one to six        fluorine atoms or with from one to three substituents        independently selected from the group R^(1a);    -   R⁸ is selected from —H and —C₁-C₆ alkyl;    -   or, when Z is —C(═NR⁸)CHR¹R², R⁸ and R¹ may together with the        nitrogen and carbon atoms to which they are respectively        attached optionally form a five to fourteen membered heteroaryl        ring or a five to eight membered heterocycloalkyl ring, wherein        said heteroaryl or heterocycloalkyl ring optionally contains        from one to two further heteroatoms selected from N, O and S,        and wherein said heterocycloalkyl ring optionally contains from        one to three double bonds, and wherein said heteroaryl or        heterocycloalkyl ring is optionally substituted with from one to        three substituents independently selected from the group R^(1b);    -   n is 0, 1, 2    -   and the pharmaceutically acceptable salts of such compounds.    -   n another embodiment, the compound of Formula I has the        following structure:

Compounds of the Formula I may have optical centers and therefore mayoccur in different enantiomeric, diastereomeric and meso configurations.The present invention includes all enantiomers, diastereomers, and otherstereoisomers of such compounds of the Formula I, as well as racemic andother mixtures thereof. The present invention also includes alltautomers of the Formula I. When the compounds of Formula I of thepresent invention contain one optical center, the “S” enantiomer ispreferred.

Insofar as the compounds of Formula I of this invention contain basicgroups, they can form acid addition salts with various inorganic andorganic acids. The present invention also relates to thepharmaceutically acceptable acid addition salts of compounds of theFormula I. Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate the base compound from the reaction mixture as apharmaceutically unacceptable salt and then simply convert to the freebase compound by treatment with an alkaline reagent, and thereafter,convert the free base to a pharmaceutically acceptable acid additionsalt. The acid addition salts of the base compounds of this inventionare readily prepared by treating the base compound with a substantiallyequivalent amount of the chosen mineral or organic acid in an aqueoussolvent or in a suitable organic solvent, such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isreadily obtained. The acids which are used to prepare thepharmaceutically acceptable acid addition salts of the aforementionedbase compounds of this invention are those which form non-toxic acidaddition salts, i.e., salts containing pharmaceutically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate,citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate,fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate))salts. Other examples ofpharmaceutically acceptable salts of the compounds of this invention arethe salts of salicylic acid, oxalic acid, di-p-toluoyl tartaric acid,mandelic acid, sodium, potassium, magnesium, calcium and lithium.

The present invention also includes isotopically-labeled compounds thatare identical to those recited in Formula I, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into the compoundsof the present invention include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, chlorine and iodine, such as ²H, ³H, ¹³C,¹¹C, ¹⁴C, ¹⁵N, 18O, ¹⁷O, ¹⁸F, ¹²³I and ¹²⁵I, respectively. The compoundsof Formula I of the present invention, prodrugs thereof,pharmaceutically acceptable salts of such compounds or of such prodrugs,and compounds and derivatives of such compounds that contain theaforementioned isotopes and/or other isotopes are within the scope ofthis invention. Such compounds may be useful as research and diagnostictools in metabolism pharmacokinetic studies and in binding assays.Certain isotopically-labeled compounds of the Formula I of the presentinvention, for example, those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically-labeled compounds of the Formula I ofthe present invention and prodrugs and derivatives thereof may generallybe prepared by carrying out the procedures disclosed in the schemes anddiscussion of the schemes and/or in the examples and preparationsdescribed herein, by substituting a readily availableisotopically-labeled reagent for a nonisotopically-labeled reagent inthe preparation of said compounds.

Unless otherwise indicated, as used herein, the terms “halogen” and“halo” include F, Cl, Br and I.

Unless otherwise indicated, as used herein, the term “alkyl” includessaturated monovalent hydrocarbon radicals having straight or branchedmoieties. Examples of alkyl groups include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene(—CH₂-cyclopropyl) and t-butyl.

Unless otherwise indicated, as used herein, the term “alkenyl” includesalkyl moieties having at least one carbon-carbon double bond whereinalkyl is as defined above. Examples of alkenyl include, but are notlimited to, ethenyl and propenyl.

Unless otherwise indicated, as used herein, the term “alkynyl” includesalkyl moieties having at least one carbon-carbon triple bond whereinalkyl is as defined above. Examples of alkynyl groups include, but arenot limited to, ethynyl and 2-propynyl.

Unless otherwise indicated, as used herein, the term “alkoxy”, means“alkyl-O—, wherein “alkyl” is as defined above. Examples of “alkoxy”groups include, but are not limited to, methoxy, ethoxy, propoxy,butoxy, pentoxy and allyloxy.

Unless otherwise indicated, as used herein, the term “alkenoxy”, means“alkenyl-O—”, wherein “alkenyl” is as defined above.

Unless otherwise indicated, as used herein, the term “alkynoxy”, means“alkynyl-O—”, wherein “alkynyl” is as defined above.

In all of the above defined “C₁-C_(x) alkyl,” “C₁-C_(x) alkenyl,”“C₁-C_(x) alkynyl,” “C₁-C_(x) alkoxy,” “C₁-C_(x) alkenoxy,” and“C₁-C_(x) alkynoxy,” groups, when x is an integer greater than 2, such“C₁-C_(x) alkyl,” “C₁-C_(x) alkenyl,” “C₁-C_(x) alkynyl,” “C₁-C_(x)alkoxy,” “C₁-C_(x) alkenoxy,” and “C₁-C_(x) alkynoxy,” groups, mayoptionally be replaced with a “polyfluoro C₁-C_(x) alkyl,” a polyfluoroC₁-C_(x) alkenyl,” a “polyfluoro C₁-C_(x) alkynyl,” a “polyfluoroC₁-C_(x) alkoxy,” a “polyfluoro C₁-C_(x) alkenoxy,” or a “polyfluoroC₁-C_(x) alkynoxy,” group. As used herein, the expression “polyfluoroC₁-C_(x) alkyl” refers to alkyl groups, as defined above, that compriseat least one —CF₂ and/or CF₃ group.

Unless otherwise indicated, as used herein, the term “cycloalkyl”includes non-aromatic saturated cyclic alkyl moieties wherein alkyl isas defined above. Examples of cycloalkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl. “Bicycloalkyl” and “tricycloalkyl” groups are non-aromaticsaturated cyclic alkyl moieties consisting of two or three rings,respectively, wherein said rings share at least one carbon atom whichmay contain a carbon bridge. For purposes of the present invention, andunless otherwise indicated, bicycloalkyl groups include spiro groups andfused ring groups. Examples of bicycloalkyl groups include, but are notlimited to, bicyclo-[3.1.0]-hexyl, bicyclo-[2.2.1]-hept-1-yl, norbornyl,spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, and spiro[4.2]heptyl.An example of a tricycloalkyl group is adamantanyl. Other cycloalkyl,bicycloalkyl, and tricycloalkyl groups are known in the art, and suchgroups are encompassed by the definitions “cycloalkyl”, “bicycloalkyl”and “tricycloalkyl” herein. “Cycloalkenyl“, “bicycloalkenyl” and“tricycloalkenyl” refer, respectively, to non-aromatic cycloalkyl,bicycloalkyl and tricycloalkyl moieties, respectively, as defined above,except that they each include one or more carbon-carbon double bondsconnecting carbon ring members (an ∓endocyclic” double bond) and/or oneor more carbon-carbon double bonds connecting a carbon ring member andan adjacent non-ring carbon (an “exocyclic” double bond). Examples ofcycloalkenyl groups include, but are not limited to, cyclopentenyl,cyclobutenyl, and cyclohexenyl. A non-limiting example of abicycloalkenyl group is norbornenyl. Cycloalkyl, cycloalkenyl,bicycloalkyl, and bicycloalkenyl groups also include groups that aresubstituted with one or more oxo moieties. Examples of such groups withoxo moieties are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl andnorcamphoryl. Other cycloalkenyl, bicycloalkenyl, and tricycloalkenylgroups are known in the art, and such groups are included within thedefinitions “cycloalkenyl”, “bicycloalkenyl” and “tricycloalkenyl”herein.

Unless otherwise indicated, as used herein, the term “aryl” includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl (Ph), naphthyl, indenyl, indanyl and fluorenyl.“Aryl” encompasses fused ring groups wherein at least one ring isaromatic.

Unless otherwise indicated, as used herein, the terms “heterocyclic” and“heterocycloalkyl” refer to non-aromatic cyclic groups containing one ormore heteroatoms, prefereably from one to four heteroatoms, eachindependently selected from O, S and N. “Heterobicycloalkyl” groups arenon-aromatic two-ringed cyclic groups, wherein said rings share one ortwo atoms, and wherein at least one of the rings contains a heteroatom(O, S, or N). Unless otherwise indicated, for purposes of the presentinvention, heterobicycloalkyl groups include spiro groups and fused ringgroups. In one embodiment, each ring in the heterobicycloalkyl groupcontains up to four heteroatoms (i.e. from zero to four heteroatoms,provided that at least one ring contains at least one heteroatom). Theheterocyclic groups of this invention can also include ring systemssubstituted with one or more oxo moieties. Examples of non-aromaticheterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino,thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, quinolizinyl,quinuclidinyl, 1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyl,1,4-dioxaspiro[4.3]octyl, and 1,4-dioxaspiro[4.2]heptyl.

Unless otherwise indicated, as used herein, “heteroaryl” refers toaromatic groups containing one or more heteroatoms, preferably from oneto four heteroatoms, selected from O, S and N. A multicyclic groupcontaining one or more heteroatoms wherein at least one ring of thegroup is aromatic is a “heteroaryl” group. The heteroaryl groups of thisinvention can also include ring systems substituted with one or more oxomoieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,isoquinolyl, 1,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl, thienyl,isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, triazinyl, 1,2,4-trizainyl, 1,3,5-triazinyl, isoindolyl,1-oxoisoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl,tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, andazaindolyl.

Unless otherwise indicated, as used herein, the term “cycloalkoxy”,means “cycloalkyl-O—”, wherein “cycloalkyl” is as defined above.

Unless otherwise indicated, as used herein, the term “aryloxy”, means“aryl-O—”, wherein “aryl” is as defined above.

Unless otherwise indicated, as used herein, the term“heterocycloalkoxy”, means “heterocycloalkyl-O—”, wherein“heterocycloalkyl” is as defined above.

Unless otherwise indicated, as used herein, the term “heteroaryloxy”,means “heteroaryl-O—”, wherein “heteroaryl” is as defined above.

The foregoing groups, as derived from the compounds listed above, may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). The terms referring to the groups also encompass allpossible tautomers.

In another aspect, the present invention relates to compounds of theFormula I, wherein Z is —C(═O)CHR¹R², R² is —H, —OH, or OC(═O)CH₃.

In another aspect, the present invention relates to compounds of theFormula I, wherein Z is —C(═O)C(═O)R¹.

In another aspect, the present invention relates to compounds of theFormula I, wherein Z is —SO₂R¹.

In another aspect, the present invention relates to compounds of theFormula I wherein R¹ is selected from —C₁-C₂₀ alkyl, —C₂-C₂₀ alkenyl,—C₂-C₂₀ alkynyl, —C₃-C₂₀ cycloalkyl, (4-20 membered) heterocycloalkyl,—C₆-C₂₀ aryl and (5-20 membered) heteroaryl.

In another aspect, R¹ is selected from —C₁-C₁₀ alkyl, —C₂-C₁₀ alkenyl,—C₃-C₁₀ cycloalkyl, phenyl, thienyl and pyridyl, wherein R¹ isoptionally independently substituted with from one to two substituentsindependently selected from —C₁-C₄ alkyl, —OCF₃, —CF₃, —C₁-C₄ alkoxy,—F, —Cl, —Br, phenyl and phenoxy, wherein R¹ optionally contains one ortwo double or triple bonds.

In another aspect, R¹ is —C₃-C₇cycloalkyl, e.g., [2.2.1]-heptanyl.

In another aspect, R¹ is selected from phenyl and pyridyl, wherein R¹ isoptionally independently substituted with from one to two substitutentsindependently selected from —F, —Cl, OCF₃, and —CF₃.

In another aspect, the present invention relates to compounds of theFormula I wherein R² is selected from —H, —OH, and —OC(═O)CH₃.

In another aspect, R² is selected from —H and —OH.

In another aspect, R² is selected from —OC(═O)CH₃.

In another aspect, the present invention relates to compounds of theFormula I wherein R³ is selected from —C₁-C₄ alkyl, allyl, and—CH₂CH₂SCH₃.

In another aspect, the present invention relates to compounds of theFormula I wherein R⁵ is H.

In another aspect, the present invention relates to compounds of theFormula I wherein R⁷ is selected from —H, —C₁-C₁₂ alkyl, —C₂-C₁₂alkenyl, —C₁-C₂₀ alkoxy, —F, —Cl, —Br, —I, —CN, —NO₂, —C₃-C₁₅cycloalkyl, -(3-15 membered) heterocycloalkyl, —C₆-C₁₅ aryl, -(5-15membered) heteroaryl, —CHO, —C(═O)(C₁-C₁₅ alkyl), —C(═O)((5-15membered)heterocycloalkyl), —C(═O)((5-15 membered) heteroaryl),—C(═O)O(C₁-C₈ alkyl), —C(═O)N(C₁-C₁₀ alkyl)(C₁-C₁₀ alkyl),—S(O)_(n)-alkyl, —S(O)_(n)-cycloalkyl, —S(O)_(n)-(6 to 14 membered)aryl, —S(O)_(n)-(5 to 14 membered) heteroaryl, wherein said alkyl,cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionallyindependently substituted with from one to three substituentsindependently selected from —F, —Cl, —Br, —I, —OH, —C₁-C₆ alkoxy, —C₂-C₆alkenoxy, —C₂-C₆ alkynoxy, —NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)R¹¹, —C(═O)OR¹²,—C(═O)NR⁹R¹⁰, —S(O)_(n)NR⁹R¹⁰—C₃-C₁₅ cycloalkyl, -(4-15 membered)heterocycloalkyl, —C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, (5-15membered) heterocycloalkoxy, —C₆-C₁₂ aryloxy and (6-12 membered)heteroaryloxy.

In another aspect, wherein R⁷ is selected from —H, —C₁-C₁₂ alkyl,—C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —C₁-C₂₀ alkoxy, —F, —Cl, —Br, —I, —CN,—NO₂, —(C_(zero)-C₄alkylene)(C₃-C₁₅cycloalkyl), -(3-15 membered)heterocycloalkyl, —C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, —CHO,—C(═O)(C₁-C₁₅ alkyl), —C(═O)((5-15 membered) heterocycloalkyl),—C(═O)(C₅-C₁₅ aryl), —C(═O)((5-15 membered) heteroaryl), —C(═O)(C₅-C₁₅cycloalkyl), —C(═O)O(C₁-C₈ alkyl), —C(═O)N(C₁-C₁₀ alkyl)(C₁-C₁₀ alkyl),—C(═O)N(C_(zero)-C₁₀ alkyl)(C₆-C₁₀ aryl), —C(═O)N(C_(zero)-C₁₀alkyl)((5-10 membered) heteroaryl), —C(═O)N(C_(zero)-C₁₀ alkyl)((5-10membered) heterocycloalkyl), —C(═O)N(C_(zero)-C₁₀ alkyl)(C₅-C₁₀cycloalkyl), —S(O)_(n)—(C₁-C₆ alkyl), —S(O)_(n)—(C₃-C₈ cycloalkyl),—S(O)_(n)—(C₆-C₁₀ aryl), —S(O)_(n)-((5-10 membered) heteroaryl), whereinsaid alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl are each optionally independently substituted with from oneto three substituents independently selected from —F, —Cl, —Br, —I, —OH,—C₁-C₁₀ alkoxy, —C₂-C₁₀ alkenoxy, —C₂-C₁₀ alkynoxy, —NR⁹R¹⁰, (C₁-C₁₁alkyl)-NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)R¹¹, —C(═O)OR¹², —C(═O)NR⁹R¹⁰,—S(O)_(n)NR⁹R¹⁰—C₃-C₁₅ cycloalkyl, -(4-15 membered) heterocycloalkyl,—C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, -(4-12 membered)heterocycloalkoxy, —C₆-C₁₂ aryloxy and -(6-12 membered) heteroaryloxy.

In another aspect, R⁷ is selected from —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl,-C₂-C₁₂ alkynyl, —(C_(zero)-C₄ alkylene)(C₃-C₁₅ cycloalkyl), and—(C_(zero)-C₄ alkylene)(4-15 membered) heterocycloalkyl, wherein saidalkyl, alkenyl, cycloalkyl and heterocycloalkyl are each optionallyindependently substituted with from one to three substitutentsindependently selected from —OH, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆alkynoxy and —NR⁹R¹⁰.

In another aspect, R⁷ is selected from —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl,—C₃-C₁₅ cycloalkyl and -(4-15 membered) heterocycloalkyl, wherein saidalkyl, alkenyl, cycloalkyl and heterocycloalkyl are each optionallyindependently substituted with from one to three substitutentsindependently selected from —OH, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆alkynoxy.

In another aspect, R⁷ is selected from —C₁-C₁₂ alkyl, —C₂-C₁₂-alkenyland —C₃-C₁₅ cycloalkyl, wherein said alkyl, alkenyl and cycloalkyl areeach optionally independently substituted with from one to threesubstitutents NR⁹R¹⁰.

In another aspect, R⁷ is -(4-15 membered) heterocycloalkyl, wherein saidheterocycloalkyl is optionally substituted with from one to threesubstitutents independently selected from —OH, —C₁-C₆ alkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆alkynoxy, —(C₆-C₁₀ aryl) and -(5-15 membered) heteroaryl.

Non-limiting examples of the compound of formula I include the followingcompounds:

-   -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(4-methoxy-phenyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3,4-dimethyl-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-adamantan-1-yl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-phenyl-propylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-trifluoromethyl-benzylsulfanyl)-thiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-methoxy-benzylsulfanyl)-thiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-fluoro-benzylsulfanyl)-thiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-propylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[2-(3-trifluoromethyl-phenoxy)-ethylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3,4-dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-dipropylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-benzylsulfanyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(2,4-dichloro-phenoxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(4-phenoxy-butylsulfanyl)-thiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[2-(4-bromo-phenoxy)-ethylsulfanyl]-thiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-diethylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-ethylsulfamoyl-[1,3,4]thiadiazol-2-yl )-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-phenethylsulfanyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic        acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic        acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-(S)-hydroxy-acetylamino]-pentanoic        acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid        (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)-pentanoic acid        (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-(S)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-(R)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;    -   Hydroxy-phenyl-acetic acid        [1-(5-methyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butylcarbamoyl]-phenyl-methyl        ester;    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic        acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-(R)-2-hydroxy-acetylamino]-pentanoic        acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-formyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(2,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2,4,4-trimethyl-pentyl )-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-(S)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-(R)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-(S)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-(R)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-(S)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-(R)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;

2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;

-   -   2-(2-(S)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-(R)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-isopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(S)-2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic        acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(R)-2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic        acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3-Trifluoromethoxy-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;

3-(5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-yl)-3-methyl-butyricacid;

-   -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-2-oxiranyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-but-3-enyl)-3-oxy-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1,1-dimethyl-3-(2,2,2-trifluoro-ethylamino)-propyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-butyl)-1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-isopropylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3,3-dimethoxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-ethylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-isopropylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-hydroxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-isopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-ethylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-(R)-2-hydroxy-acetylamino]-pentanoic        acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic        acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-dimethylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-propylamino-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[3-(2-hydroxy-ethylamino)-1,1-dimethyl-propyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-tert-butylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-cyclopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-morpholin-4-yl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[3-(1-ethyl-propylamino)-1,1-dimethyl-propyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        [5-(3-cyclopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-hydroxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic        acid        (5-{3-[formyl-(2,2,2-trifluoro-ethyl)-amino]-1,1-dimethyl-propyl}-[1,3,4]thiadiazol-2-yl)-amide    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        (5-{3-[formyl-(2,2,2-trifluoro-ethyl)-amino]-1,1-dimethyl-propyl}-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-chloro-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-(5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino)-[1,3,4]thiadiazol-2-ylsulfanyl)-2-methyl-propionic        acid ethyl ester;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[(isopropyl-phenyl-carbamoyl)-methylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-fluoro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-allyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-propenyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-acetyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(3-methyl-butylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-butylamino-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(3,3-dimethyl-butylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-cyclopropylamino-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(4-methyl-piperazin-1-yl)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(4-chloro-benzylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(3-chloro-benzylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-benzyloxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-ethylsulfanyl-[1,3,4]thiadiazol-2-yl)-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(2-dimethylamino-ethylsulfanyl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-ethoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-dimethylamino-[1,3,4]thiadiazol-2-yl)-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isobutyl-[1,3,4]thiadiazol-2-yl)-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-phenyl-[1,3,4]thiadiazol-2-yl)-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl        )-butyramide;    -   N-(5-Benzyl-[1,3,4]thiadiazol-2-yl)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-phenoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;

N-[5-(3-Chloro-phenyl)-[1,3,4]thiadiazol-2-yl]-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;

-   -   N-(5-Cyclobutyl-[1,3,4]thiadiazol-2-yl)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]thiadiazol-2-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-methoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isopropylsulfanyl-[1,3,4]thiadiazol-2-yl)-butyramide;    -   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid        (5-cyclohexyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid        (5-methylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-(5-{2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-ylsulfanyl)-propionic        acid ethyl ester;    -   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid        (5-phenethyl-[1,3,4]thiadiazol-2-yl)-amide;    -   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid        [5-(1-phenoxy-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[3-(toluene-4-sulfonylamino)-[1,2,4]thiadiazol-5-yl]-butyramide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (3-ethylsulfanyl-[1,2,4]thiadiazol-5-yl)-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (3-methanesulfonyl-[1,2,4]thiadiazol-5-yl)-amide; and    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [3-(4-nitro-benzenesulfonylamino)-[1,2,4]thiadiazol-5-yl]-amide.

Compounds of the Formula I of this invention, and their pharmaceuticallyacceptable salts, have useful pharmaceutical and medicinal properties.The compounds of Formula I, and their pharmaceutically acceptable saltsinhibit the production of Aβ-peptide (thus, gamma-secretase activity) inmammals, including humans. Compounds of the Formula I, and theirpharmaceutically acceptable salts, are therefore able to function astherapeutic agents in the treatment of the neurodegenerative and/orneurological disorders and diseases enumerated below, for exampleAlzheimer's disease, in an afflicted mammal, including a human.

The present invention also relates to a pharmaceutical composition forinhibiting or modulating Aβ-peptide production in a mammal, including ahuman, comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis and Down's Syndrome in a mammal,including a human, comprising an amount of a compound of the Formula I,or a pharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-peptide production, and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-peptide production, and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or a condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis and Down's Syndrome in a mammal,including a human, comprising an amount of a compound of the Formula I,or a pharmaceutically acceptable salt thereof, that is effective intreating such disease or condition, and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or a condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disease or condition, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of inhibiting Aβ-peptideproduction in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease, hereditary cerebralhemorrhage with amyloidosis, cerebral amyloid angiopathy, aprion-mediated disease, inclusion body myositis, stroke, multiplesclerosis and Down's Syndrome in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the Formula I,or a pharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease and Down's Syndrome in amammal, including a human, comprising administering to said mammal anamount of a compound of the Formula I, or a pharmaceutically acceptablesalt thereof, that is effective in inhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease, hereditary cerebralhemorrhage with amyloidosis, cerebral amyloid angiopathy, aprion-mediated disease, inclusion body myositis, stroke, multiplesclerosis and Down's Syndrome in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the Formula I,or a pharmaceutically acceptable salt thereof, that is effective intreating such condition.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease and Down's Syndrome in amammal, including a human, comprising administering to said mammal anamount of a compound of the Formula I, or a pharmaceutically acceptablesalt thereof, that is effective in treating such condition.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition associated with Aβ-peptide production ina mammal, including a human, comprising (a) a compound of the Formula I,or a pharmaceutically acceptable salt thereof; (b) a memory enhancementagent, antidepressant, anxiolytic, antipsychotic agent, sleep disorderagent, anti-inflammatory agent, anti-oxidant agent, cholesterolmodulating agent or anti-hypertensive agent; and (c) a pharmaceuticallyacceptable carrier; wherein the active agents “a” and “b” above arepresent in amounts that render the composition effective in treatingsuch disease or condition.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis and Down's Syndrome, in a mammal,including a human, comprising (a) a compound of the Formula I, or apharmaceutically acceptable salt thereof; (b) a memory enhancementagent, antidepressant, anxiolytic, antipsychotic agent, sleep disorderagent, anti-inflammatory agent, anti-oxidant agent, cholesterolmodulating agent or anti-hypertensive agent; and (c) a pharmaceuticallyacceptable carrier; wherein the active agents “a” and “b” above arepresent in amounts that render the composition effective in treatingsuch disease or condition.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome, in a mammal, including a human,comprising (a) a compound of the Formula I, or a pharmaceuticallyacceptable salt thereof; (b) a memory enhancement agent, antidepressant,anxiolytic, antipsychotic agent, sleep disorder agent, anti-inflammatoryagent, anti-oxidant agent, cholesterol modulating agent oranti-hypertensive agent; and (c) a pharmaceutically acceptable carrier;wherein the active agents “a” and “b” above are present in amounts thatrender the composition effective in treating such disease or condition.

The present invention also relates to a method of treating a disease orcondition associated with Aβ-peptide production in a mammal, including ahuman, comprising administering to said mammal (a) a compound of theFormula I, or a pharmaceutically acceptable salt thereof; and (b) amemory enhancement agent, antidepressant, anxiolytic, antipsychoticagent, sleep disorder agent, anti-inflammatory agent, anti-oxidantagent, cholesterol modulating agent or anti-hypertensive agent; whereinthe active agents “a” and “b” above are present in amounts that renderthe composition effective in treating such disease or condition.

The present invention also relates to a method of treating a disease orcondition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis and Down's Syndrome, in a mammal, including a human,comprising administering to said mammal (a) a compound of the Formula I,or a pharmaceutically acceptable salt thereof; and (b) a memoryenhancement agent, antidepressant, anxiolytic, antipsychotic agent,sleep disorder agent, anti-inflammatory agent, anti-oxidant agent,cholesterol modulating agent or anti-hypertensive agent; wherein theactive agents “a” and “b” above are present in amounts that render thecomposition effective in treating such disease or condition.

The present invention also relates to a method of treating a disease orcondition selected from the group consisting of Alzheimer's disease andDown's Syndrome, in a mammal, including a human, comprisingadministering to said mammal (a) a compound of the Formula I, or apharmaceutically acceptable salt thereof; and (b) a memory enhancementagent, antidepressant, anxiolytic, antipsychotic agent, sleep disorderagent, anti-inflammatory agent, anti-oxidant agent, cholesterolmodulating agent or anti-hypertensive agent; wherein the active agents“a” and “b” above are present in amounts that render the compositioneffective in treating such disease or condition.

Compounds of the Formula I may be used alone or used as a combinationwith any other drug, including, but not limited to, any memoryenhancement agent, e.g., Aricept™, antidepressant agent, e.g., Zoloft™,anxiolytic, antipsychotic agent, e.g., Geodon™, sleep disorder agent,anti-inflammatory agent, e.g., Celebrex™, Bextra™, etc., anti-oxidantagent, cholesterol modulating agent (for example, an agent that lowersLDL or increases HDL), e.g., Lipitor™, or anti-hypertension agent.Accordingly, this invention also provides a pharmaceutical compositionfor treatment of a mammal, including a human, in need thereof comprisingan effective amount of a compound of the Formula I and an effectiveamount of another drug, for example a memory enhancement agent, e.g.,Aricept™, antidepressant agent, e.g., Zoloft™, anxiolytic, antipsychoticagent, e.g., Geodon™, sleep disorder agent, anti-inflammatory agent,e.g., Celebrex™, Bextra™, etc., anti-oxidant agent, cholesterolmodulating agent (for example, an agent that lowers LDL or increasesHDL), e.g., Lipitor™, or anti-hypertension agent, and a pharmaceuticallyacceptable carrier. This invention also provides a method for treatingdementia, for example Alzheimer's disease, in a mammal, including in ahuman, comprising administering to the mammal an effective amount of acompound of the Formula I and an effective amount of another drug, forexample a memory enhancement agent, e.g., Aricept™, antidepressantagent, e.g., Zoloft™, anxiolytic, antipsychotic agent, e.g., Geodon™,sleep disorder agent, anti-inflammatory agent, e.g., Celebrex™, Bextra™,etc., anti-oxidant agent, cholesterol modulating agent (for example, anagent that lowers LDL or increases HDL), e.g., Lipitor™, oranti-hypertension agent.

Compounds of the Formula I, or any of the combinations described in theimmediately preceding paragraph, may optionally be used in conjunctionwith a know P-glycoprotein inhibitor, such as verapamil.

References herein to diseases and conditions “associated with Aβ-peptideproduction” relate to diseases or conditions that are caused, at leastin part, by Aβ-peptide and/or the production thereof. Thus, Aβ-peptideis a contributing factor, but not necessarily the only contributingfactor, to “a disease or condition associated with Aβ-peptideproduction.”

As used herein, the term “treating” refers to reversing, alleviating orinhibiting the progress of a disease, disorder or condition, or one ormore symptoms of such disease, disorder or condition, to which such termapplies. As used herein, “treating” may also refer to decreasing theprobability or incidence of the occurrence of a disease, disorder orcondition in a mammal as compared to an untreated control population, oras compared to the same mammal prior to treatment. For example, as usedherein, “treating” may refer to preventing a disease, disorder orcondition, and may include delaying or preventing the onset of adisease, disorder or condition, or delaying or preventing the symptomsassociated with a disease, disorder or condition. As used herein,“treating” may also refer to reducing the severity of a disease,disorder or condition or symptoms associated with such disease, disorderor condition prior to a mammal's affliction with the disease, disorderor condition. Such prevention or reduction of the severity of a disease,disorder or condition prior to affliction relates to the administrationof the composition of the present invention, as described herein, to asubject that is not at the time of administration afflicted with thedisease, disorder or condition. As used herein “treating” may also referto preventing the recurrence of a disease, disorder or condition or ofone or more symptoms associated with such disease, disorder orcondition. The terms “treatment” and “therapeutically,” as used herein,refer to the act of treating, as “treating” is defined above.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the Formula I, and their pharmaceutically acceptable salts,may be prepared as described in the following reaction Schemes anddiscussion. Unless otherwise indicated, as referred to in the reactionschemes and discussion that follow, R¹, R^(1a), R^(1b), R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², Z, and n are as defined above.

The compounds of Formula I may have asymmetric carbon atoms and maytherefore exist as racemic mixtures, diastereoisomers, geometricisomers, or as individual optical isomers.

Separation of a mixture of isomers of compounds of Formula I into singleisomers may be accomplished according to conventional methods known inthe art.

The compounds of the Formula I may be prepared by the methods describedbelow, together with synthetic methods known in the art of organicchemistry, or modifications and derivatizations that are familiar tothose of ordinary skill in the art. Preferred methods include, but arenot limited to, those described below.

The reactions described below are performed in solvents that areappropriate to the reagents and materials employed and that are suitablefor use in the reactions described. In the description of the syntheticmethods described below, it is also to be understood that all reactionconditions, whether actual or proposed, including choice of solvent,reaction temperature, reaction duration time, reaction pressure, andother reaction conditions (such as anhydrous conditions, under argon,under nitrogen, etc.), and work up procedures, are those conditions thatare standard for that reaction, as would be readily recognized by one ofskill in the art. Alternate methods may also be used.

Scheme I refers to a method of preparation of compounds of the FormulaI, 10. An amino-thiadiazole 1 is coupled with a nitrogen-protected aminoacid 2a-c using conventional coupling reagents and procedures. Thenitrogen protecting group may be a carbamate-type such as butoxycarbonyl(“BOC”, P═O-tert-butyl) or benzyloxycarbonyl (“CBZ”, P═O-benzyl) that isprepared with either di-tert-butyl dicarbonate (Aldrich ChemicalCompany, Milwaukee Wis.), or benzyl chloroformate (Aldrich) in thepresence of either an inorganic or organic base (e.g., sodium carbonateor triethylamine) at 0 to 30° C. in an organic solvent (e.g., methylenechloride) or in a mixture of water and an organic solvent (e.g., ethylacetate) (see, Muller, Methoden Der Oraanischen Chemie. “VierteAuglage—Synthesis von Peptiden I”—Houben Weyl—Georg-Thieme VerlagStuttgart, 1974, Band XV/1).

The amino-thiadiazoles 1 starting reagents may be prepared according tothe procedure similar to the known in literature (references ActaUniversitatis Palackianae Olomucensis, Facultas Rerum Naturalium,Chemica (2001); Journal of Medicinal Chemistry (2003), 46(3), 427-440.European Journal of Medicinal Chemistry (2002), 37(8), 689-697.Phosphorus, Sulfur and Silicon and the Related Elements (2002), 177(4),863-875. Chemistry of Heterocyclic Compounds (New York, N.Y., UnitedStates)(Translation of Khimiya Geterotsiklicheskikh Soedinenii) (2001),37(9), 1102-1106. Journal of the Institution of Chemists (India) (2001),73(3), 108-110. Russian Journal of General Chemistry (Translation ofZhurnal Obshchei Khimii) (2000), 70(11), 1801-1803. Indian Journal ofChemistry, Section B: Organic Chemistry Including Medicinal Chemistry(1989), 28B(1), 78-80. Indian Journal of Chemistry, Section B: OrganicChemistry Including Medicinal Chemistry (1981), 20B(6), 518-20. KhimiyaGeterotsiklicheskikh Soedinenii, (10), 1416-19; 1986. Journal of theInstitution of Chemists (India), 61(2), 54-6; 1989 Journal of theInstitution of Chemists (India), 73(5), 193-195; 2001. Chimica ActaTurcica (1984), 12(2), 305-14. Journal of Heterocyclic Chemistry, 21(6),1689-98; 1984. Journal of Heterocyclic Chemistry (1980), 17(3), 607-8.Journal of Heterocyclic Chemistry (1969), 6(6), 835-40. Huaxue Shijie(2002), 43(7), 366-368. Indian Journal of Chemistry (1970), 8(6),509-13. Ber. (1942), 75B 87-93. Journal of Medicinal Chemistry (1970),13(5), 1015-17. Farmaco, Edizione Scientifica (1971), 26(1), 19-28.Journal of the Indian Chemical Society (1989), 66(2), 118-19. Journal ofHeterocyclic Chemistry, 12(3), 581-3; 1975 European Journal of MedicinalChemistry, 10(2), 121-4; 1975. Journal of Heterocyclic Chemistry (1977),14(5), 853-5. Zhurnal Obshchei Khimii (1980), 50(4), 860-3. EuropeanJournal of Medicinal Chemistry (1996), 31(7-8), 597-606. Journal ofHeterocyclic Chemistry (1980), 17(3), 607-8. Journal fuer PraktischeChemie (Leipzig), 332(1), 55-64; 1990 ). For example, compounds offormula 1 can be obtained by reacting a compound of formula VlI-IX, withthiosemicarbazide in a suitable solvent such as water, C1-C4 alcohol inthe presence of acid, preferably HCl, H₃PO₄, polyphosphoric acid,sulfuric acid, MeSO₃OH, et.c. . Compounds of formula 1 can also beobtained by reacting a compound of formula X with FeCl₃ as described inthe reference cited above (Journal of Heterocyclic Chemistry, 12(3),581-3; 1975; Pharm. Pharmacol. Commun. 2000, 6, 31-33; Russian J. Org.Chem. Vol 33, 1997, pp567-568; Eur. J. Med. Chem (1996) 31, 597-606;).Alternatively, compounds of formula 1 can be obtained by reacting acompound of formula VII, with thiosemicarbazide and phosphorousoxychloride at reflux, followed by hydrolysis (J. Heterocyclic Chem. 8:835-837.).

Numerous reagents that are well-known in the art may be used to couple 1and 2a-c to form 3 by standard peptide coupling methods (2a) or thetrimethylaluminum coupling method (2b) or a leaving group (halogen or amixed anhydride)(2c) known in art of organic chemistry (Scheme I).Activation of the carboxylic acid 2a with oxalyl halide, thionylchloride, carbodiimidazole, or chloro-(C₁-C₄)alkyl-formate, in theprepsence of an appropriate base (e.g., tialkylamine, pyridine,dimethylaminopyridine or sodium carbonate, or the like) or carbodiimideswith or without the use of known additives such as N-hydroxysuccinimide,1-hydroxybenzotriazole, etc. can be used to facilitate coupling.Standard coupling agents include HATU(O-(7-azabenzotriazole-1y)-1,1,3,3,-tetramethyluroniumhexafluorophosphate) or PyBOP(benzotriazole-1-yl)-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate) or HBTU(O-benzotriazole-1yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate)/trialkylamine, or 1-hydroxybenzotriazole(HOBT)/1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride(EDAC)/trialkylamine (NEt3), in an appropriate solvent such as methylenechloride, chloroform, tetrahydrofuran (THF), acetonitrile,dimethylforamide (DMF), and the like or a mixture of two solvents tohave reagents mixed well to form a clear solution. Peptide couplingagents or resins for solid phase synthesis such as Fmoc(Fluorenylmethylcarbonyl)-protected hydroxylamine bound to polystylenebeads are common and well known in the literature. Deprotection of theFmoc group under standard conditions using 20% piperidine in DMF.References: O-benzotriazol-1-yl-N,N,N,′N′-tetramethyluroniumhexafluorophosphate (“HBTU”, Aldrich Chemical Company) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (“HATU”, Aldrich) (See, Fieser, Reagents for OrganicSynthesis, 1986, Wiley Interscience, New York, Vol.12, p. 44; Hruby,Biorganic Chemistry: Peptides and Proteins, 1998, Oxford Universitypress, New York, pp. 27-64; Muller, Methoden Der Organischen Chemie,Vierte Auflage—Synthese von Peptiden II—Houben Weyl, George-ThiemeVerlag Stuttgart, 1974, Band XV/2). When optically active reagents areemployed, reaction conditions, such as temperature, time and theselection of the base, must be carefully controlled to avoidracemization. The protected amino group or carboxylic acid group may beprepared by methods well known in the literature for amino acidprotecting groups as described in Organic chemistry Journal, textbooksuch as “Protective Groups in Organic Syntehsis” by T. W. Green.Alternatively, the coupling can be performed by reacting 1 with an ester2b in the presence of trialkylaluminum in an appropriate solvent, eg.,THF, dioxane, toluene or a mixture of THF/toluene in an open or sealedtube at a temperature between 0° C.-120° C. until the completeconversion to the desired product (3 in Scheme I); preferred temperatureis room temperature to 80° C.

Intermediate 3 of Scheme I, is deprotected to afford aminoamide 4 eitherthrough treatment with strong acid in the case of t-butoxycarbonyl orthrough hydrogenolysis in the case of carbobenzyloxycarbonyl.Specifically, t-BOC-3, on treatment with hydrochloric acid ortrifluoroacetic acid in an organic solvent (e.g., dioxane, THF, ormethylene chloride), at room temperature to 30° C. for about 1 hour toabout 19 hours, affords the corresponding salts 4. Alternatively, CBZ-3may be deprotected through catalytic hydrogenolysis in the presence ofhydrogen (from about 1 to about 10 atmospheres), a heavy metal catalyst(e.g., palladium on carbon or palladium hydroxide on carbon, 1 to 10percent catalyst loading, present at about 0.01 to about 0.50 times theof substrate), and a solvent (e.g., methanol, ethanol or ethyl acetate)at 20 to 50° C. for about 1 hour to about 19 hours.

The compound Formula I 10 in Scheme I may be prepared by the reaction of4 with 9 where L is a leaving group (e.g., halide, mesylate, ortriflate) and Z is as defined above. The reaction is carried out at 0 to30° C. in an organic solvent (e.g., methylene chloride, ethyl acetate,or DMF) in the presence of an organic base (e.g., triethylamine,diisopropylethylamine, or N-methylmorpholine) for about 1 minute toabout 24 hours.

Alternatively, the compound Formula I 10 may be prepared according tothe procedure of Scheme II (Z-L is a carboxylic acid or L is a leavinggroup), employing the general conditions described for Scheme I. InScheme II, R can be alkyl or benzyl. The coupling of 9 and 11 in SchemeII may be performed at a temperature of about 0 to 30° C. in an organicsolvent (e.g., methylene chloride, dichloroethane, ethyl acetate, orDMF) in the presence of a base (e.g., triethylamine ordiisopropylethylamine). When R is alkyl, either acidic or basichydrolysis may be used to covert 12 to 13. If R is benzyl, catalytichydrogenolysis may also be used to prepare 13.

The above amide bond formation may be achieved by coupling the ester (12in Scheme II) with 1 in the presence of trialkylaluminum (e.g., AlMe3)in an appropriate solvent, e.g., THF, toluene or a mixture ofTHF/toluene, or similar like solvents in an open or sealed tube at atemperature of about 0° C.-110° C. until there is complete conversion tothe desired product (10 in Scheme II). Preferably, the temperature isabout room temperature to about 80° C.

The ester group of R⁷ may be converted to the corresponding amide usinga coupling method similar to those described in Scheme I and II foramide bond formation (acid and amine with coupling agents to form anamide), or employing trimethylaluminum in an appropriate solvent or amixture of solvents, such as THF/toluene to the corresponding amide(ester with an amine to form an amide). The olefin containing R7 groupmay be converted to a ketone, CHO, CH2OH, or COOH using ozonolysisfollowed by either reduction to give alcohol (by quenching with BH3.DMS,Journal of Organic Chemistry (1989), 54(6), 1430-2.), or ketone oraldehyde (by quenching with dimethylsulfide or triphenylphosphine).

The keto or formyl group of R⁷ may be converted to the correspondingamine using a well-established reductive amination method by reacting aketone with an appropriate amine with or without acid catalyst or Lewisacid catalyst (Ti(iPrO)₄, ZnCl₂, NiCl₂,/sodium acetate/dry agents (suchas activated molecular sieves 4A, anhydrous Na₂SO₄ or MgSO₄), and areducing agent such as sodium triacetoxy borohydride, sodiumcyanoborohydride, sodium borohydride, Zn(BH₄)₂, Bu₃SnH, Bu₂SnClH,Bu₂SnIH, decaborane, silical gel-Zn(BH₄)₂, Et₃SiH-trifluoroacetic acid,pyridine-BH3, phenylsilane-dibutyltin dichloride, or the correspondingpolymer bound-NaBH₄, polymer bound-NaBH₃CN, polymer bound-NaB(OAc)₃H, orany reducing agent (e.g., hydrogenation, Pd(OAc)₂/potassium formate,Pd/C/H₂) that is known in the literature for reducing the imine bond tothe corresponding amine in an appropriate solvent, such asdichloroethane, chloroform, 2-methoxyethyl ether, dichloroethane, DMF,THF, MeOH, ethanol, about iso-propanol, t-butanol or toluene, at atemperature between room temperature to reflux, preferably at about roomtemperature to about 65° C.

The starting materials used in the procedures of the above Schemes, thesyntheses of which are not described above, are either commerciallyavailable, known in the art or readily obtainable from known compoundsusing methods that will be apparent to those skilled in the art.

The compounds of Formula I, and the intermediates shown in the abovereaction schemes, may be isolated and purified by conventionalprocedures, such as recrystallization or chromatographic separation,such as on silica gel, either with an ethyl acetate/hexane elutiongradient, a methylene chloride/methanol elution gradient, or achloroform/methanol elution gradient. Alternatively, a reverse phasepreparative HPLC or chiral HPLC separation technique may be used.

In each of the reactions discussed or illustrated above, pressure is notcritical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5 atmospheres are generally acceptable, and ambientpressure, i.e., about 1 atmosphere, is preferred as a matter ofconvenience.

Pharmaceutically acceptable salts of the compounds of Formula I may beprepared in a conventional manner by treating a solution or suspensionof the corresponding free base or acid with one chemical equivalent of apharmaceutically acceptable acid or base. Conventional concentration orcrystallization techniques may be employed to isolate the salts.Suitable acids, include, but are not limited to, acetic, lactic,succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic,cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic,hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic and related acids. Suitable bases include,but are not limited to, sodium, potassium and calcium.

A compound of the Formula I of the present invention may be administeredto mammals via either the oral, parenteral (such as subcutaneous,intravenous, intramuscular, intrasternal and infusion techniques),rectal, intranasal, topical or transdermal (e.g., through the use of apatch) routes. In general, these compounds are most desirablyadministered in doses ranging from about 0.1 mg to about 500 mg per day,in single or divided doses (i.e., from 1 to 4 doses per day), althoughvariations will necessarily occur depending upon the species, weight,age and condition of the subject being treated, as well as theparticular route of administration chosen. However, a dosage level thatis in the range of about 0.1 mg/kg to about 5 gm/kg body weight per day,preferably from about 0.1 mg/kg to about 100 mg/kg body weight per day,is most desirably employed. Nevertheless, variations may occur dependingupon the species of animal being treated and its individual response tosaid medicament, as well as on the type of pharmaceutical formulationchosen and the time period and interval at which such administration iscarried out. In some instances, dosage levels below the lower limit ofthe aforesaid range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffects, provided that such higher dosage levels are first divided intoseveral small doses for administration throughout the day.

A compound of the Formula I of the present invention may be administeredalone or in combination with pharmaceutically acceptable carriers ordiluents by either of the routes previously indicated, and suchadministration may be carried out in single or multiple doses. Suitablepharmaceutical carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Thepharmaceutical compositions formed by combining a compound of theFormula I, or a pharmaceutically acceptable salt thereof, with apharmaceutically acceptable inert carrier, can then be readilyadministered in a variety of dosage forms such as tablets, capsules,lozenges, troches, hard candies, powders, sprays, creams, salves,suppositories, jellies, gels, pastes, lotions, ointments, aqueoussuspensions, injectable solutions, elixirs, syrups, and the like.Moreover, oral pharmaceutical compositions may be suitably sweetenedand/or flavored.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (preferably corn, potato or tapioca starch),methylcellulose, alginic acid and certain complex silicates, togetherwith granulation binders such as polyvinylpyrrolidone, sucrose, gelatinand acacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred materials in this connection include lactoseor milk sugar as well as high molecular weight polyethylene glycols.When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

For parenteral administration, solutions containing a compound of theFormula I of the present invention in either sesame or peanut oil or inaqueous propylene glycol may be employed. The aqueous solutions shouldbe suitably buffered (preferably pH greater than 8) if necessary and theliquid diluent first rendered isotonic with sufficient saline orglucose. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intraarticular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart.

The compounds of Formula I of the present invention are useful ininhibiting Aβ-peptide production (thus, gamma-secretase activity) inmammals, and therefore they are able to function as therapeutic agentsin the treatment of the aforementioned disorders and diseases in anafflicted mammal.

The ability of compounds of the Formula I of this invention, and theirpharmaceutically acceptable salts, to inhibit Aβ-peptide production(thus, gamma-secretase activity) may be determined using biologicalassays known to those of ordinary skill in the art, for example theassays described below.

The activity of compounds of the Formula I of the present invention ininhibiting gamma-secretase activity was determined in a solubilizedmembrane preparation generally according to the description provided inMcLendon et al. Cell-free assays for γ-secretase activity, The FASEBJournal (Vol. 14, December 2000, pp. 2383-2386). Using such assay,compounds of the present invention were determined to have an IC₅₀activity for inhibiting gamma-secretase activity of less than about 100micromolar.

The following Examples illustrate the present invention. It is to beunderstood, however, that the invention, as fully described herein andas recited in the claims, is not intended to be limited by the detailsof the following Examples.

Experimental Procedures EXAMPLE 12-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide

A mixture of 3,5-di-fluoro-phenyl acetic acid (51.6 mg, 0.3 mmol),2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide (88mg, 0.3 mmol), HBOT (43 mg, 0.315 mmol), EDC HCl (69 mg, 0.36 mmol.) andtriethylamine (0.17 ml) in methylene chloride was stirred at roomtemperature until product formation or disappearance of startingmaterial. The mixture was quenched with water and extracted withmethylene chloride. The organic layer was separated, washed with diluteHCl, brine, dried over sodium sulfate and the solvent was removed atreduced pressure to provide the title compound as a cude oil. The oilwas purified by Shimadzu HPLC to provide the title compound as a whitesolid (56 mg), LC-MS M+1=411.2, 1 H NMR(CDCL3) 8.7 (d,1 H,NH),6.73(m,2H), 6.6(m,1 H), 4.7(m,1H), 3.5(Abq, 2H), 1.6-1.9(m,2H),1.3-1.6(m,2H), 1.5(s,9H), 0.92(t,3H) ppm.

EXAMPLE 2 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(2-phenyl-propylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide

A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid(25.4 mg, 0.2 mmol),5-(2-phenyl-propylsulfanyl)-[1,3,4]thiadiazol-2-ylamine (50 mg, 0.2mmol), HBOT (29 mg, 0.21 mmol), EDC HCl (46 mg, 0.24 mmol.) andtriethylamine (0.12 ml) in methylene chloride was stirred at roomtemperature until product formation or disappearance of startingmaterial. The mixture was quenched with water and extracted withmethylene chloride. The organic layer was separated, washed with diluteHCl, brine, dried over sodium sulfate and the solvent was removed atreduced pressure to provide the title compound as a cude oil. The oilwas purified by Shimadzu HPLC to provide the title compound as a lightyellow solid (26 mg), LC-MS M+1=505.0

EXAMPLE 3 2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide

A mixture of 2-(S)-hydroxyl-3-methyl-butyric acid (35.4 mg, 0.3 mmol),2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide (88mg, 0.3 mmol), HBOT (43 mg, 0.21 mmol), EDC HCl (69 mg, 0.36 mmol.) andtriethylamine (0.17 ml) in 2 ml of methylene chloride was stirred atroom temperature until product formation or disappearance of startingmaterial. The mixture was quenched with water and extracted withmethylene chloride. The organic layer was separated, washed with diluteHCl, brine, dried over sodium sulfate and the solvent was removed atreduced pressure to provide the title compound as a cude oil. The oilwas purified by Shimadzu HPLC to provide the title compound as a lightyellow solid (44 mg), LC-MS M+1=357.1

The following compounds were prepared by the methods analogous to thosedescribered in Examples 1, 2, or 3.

-   -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-phenyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=431.1    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(4-methoxy-phenyl)-[1,3,4]thiadiazol-2-yl]-amide, M+1=461.0,        RT=2.7 min    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3,4-dimethyl-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide,        M+1=504.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-adamantan-1-yl-[1,3,4]thiadiazol-2-yl)-amid, M+1=489.1    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-amide, M+=478.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-trifluoromethyl-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide,        M+1=545.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-methoxy-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide,        M+1=507.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-fluoro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide,        M+1=495.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-propylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=476.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[2-(3-trifluoromethyl-phenoxy)-ethylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide,        M+1=574.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3,4-dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide,        M+1=544.8    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-dipropylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=518.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-benzylsulfanyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=476.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(2,4-dichloro-phenoxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide,        M+1=543.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(4-phenoxy-butylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide,        M+1=535.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[2-(4-bromo-phenoxy)-ethylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide,        M+1=586.8    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-diethylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=490.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-ethylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=461.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-phenethylsulfanyl-[1,3,4]thiadiazol-2-yl)-amide, M+=491.0    -   2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=391.2    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=371.2    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=357.2    -   2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic        acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=427.2    -   2-[2-(3,5-Difluoro-phenyl)-2-(R)-2-hydroxy-acetylamino]-pentanoic        acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=427.2    -   2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=454.2    -   2-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=393.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=383.2    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=329.2    -   2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid        (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=428.2    -   2-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)-pentanoic acid        (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=365.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=369.1    -   2-(S)-(2-(S)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=349.1    -   2-(S)-(2-(R)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=349.1    -   Hydroxy-phenyl-acetic acid        [1-(5-methyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butylcarbamoyl]-phenyl-methyl        ester, M+1=483.2    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=329.2    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=315.1    -   2-(S)-[2-(R)-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic        acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=385.2    -   2-(S)-[2-(S)-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic        acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=385.2    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-ethylsulfanyl-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.3 min, M+1=401.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(2-dimethylamino-ethylsulfanyl)-[1,3,4]thiadiazol-2-yl]-butyramide,        RT=1.4 min, M+1=44.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-ethoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.1 min, M+1=399.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-dimethylamino-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.0 min, M+1=384.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isobutyl-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.3 min, M+1=397.4    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-phenyl-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.5 min, M+1=417.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.2 min, M+1=383.5    -   N-(5-Benzyl-[1,3,4]thiadiazol-2-yl)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide,        RT=2.5 min, M+1=431.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-phenoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.6 min, M+1=447.5    -   N-[5-(3-Chloro-phenyl)-[1,3,4]thiadiazol-2-yl]-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide,        RT=2.7 min, M+1=451.3    -   N-(5-Cyclobutyl-[1,3,4]thiadiazol-2-yl)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide,        RT=2.4 min, M+1=395.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]thiadiazol-2-yl]-butyramide,        RT=2.7 min, M+1=498.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-methoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.0 min, M+1=385.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isopropylsulfanyl-[1,3,4]thiadiazol-2-yl)-butyramide,        RT=2.6 min, M+1=415.5    -   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid        (5-cyclohexyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=493.5    -   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid        (5-methylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=504.6,        RT=2.7 min    -   2-(5-{2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-ylsulfanyl)-propionic        acid ethyl ester, M+1=543.6, RT=3.0 min    -   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid        (5-phenethyl-[1,3,4]thiadiazol-2-yl)-amide, M+1=515.4, RT=3.0        min    -   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid        [5-(1-phenoxy-ethyl)-[1,3,4]thiadiazol-2-yl]-amide, M+1=531.4,        RT=3.0 min    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        (5-methyl-[1,3,4]thiadiazol-2-yl)-amide, RT=2.0 min, M+1=385.2    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide, RT=2.3 min,        M+1=395.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-formyl-[1,3,4]thiadiazol-2-yl)-amide, RT=2.1 min, M+1=383.2    -   2-[2-(2,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide, RT=2.4 min,        M+1=411.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic        ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.6 min,        M+1=425.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-        (2,4,4-trimethyl-pentyl)-(1,3,4]thiadiazol-2-yl]-amide, RT=3.0        min, M+1=467.4    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.8 min,        M+1=453.5    -   2-(2-(S)-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.7 min,        M+1=413.5    -   2-(2-(R)-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.7 min,        M+1=413.5    -   2-(2-(R)-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.3 min,        M+1=385.5    -   2-(2-(S)-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.3 min,        M+1=385.5    -   2-(2-(R)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.2 min,        M+1=405.5    -   2-(2-(S)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.2 min,        M+1=405.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide,        RT=2.7 min, M+1=437.1    -   2-(2-(R)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.6 min,        M+1=433.5    -   2-(2-(S)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.6 min,        M+1=433.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.7        min, M+1=439.5    -   2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide, white        solid, RT=2.0 min, M+1=419.5    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide, white        solid, RT=2.6min, M+1=399.5    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide, white        solid, RT=2.4 min, M+1=385.5    -   2-[2-(3,5-Difluoro-phenyl)-2-(R)-hydroxy-acetylamino]-pentanoic        acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide,        white solid, RT=2.7 min, M+1=455.5    -   2-[2-(3,5-Difluoro-phenyl)-2-(S)-hydroxy-acetylamino]-pentanoic        acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide,        white solid, RT=2.7 min, M+1=455.5    -   2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=2.5        min, M+1=484.4    -   2-[2-(3-Trifluoromethoxy-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide, RT=3.0        min, M+1=487.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide,LC-MS        RT=2.6 min, M+1=423.2    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide,        LC-MS RT=2.4 min, M+1=409.2    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide, LC-MS RT=2.5        min, M+1=425.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-butyl)-[1,3,4]thiadiazol-2-yl]-butyramide,        LC-MS RT=2.5 min, M+1=411.4    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide,        LC-MS RT=2.6 min, M+1=423.4    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3,3-dimethoxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.6 min, M+1=485.0    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide, 1H        NMR(CDCl3) δ 7.7 (d,1H), 5.65(m,1 H), 5.1(m,2H), 4.7(m,1H),        3.8(s,1H), 2.5(d,2H), 1.7-2.0(m,2H), 1.5-1.6(m,2H), 1.45(s,6H),        0.98(s,9H), 0.94(t,3H)ppm    -   2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.6 min, M+1=416.9    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.4 min, M+1=383.0    -   2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic        acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.9 min, M+1=452.9    -   2-[2-(3,5-Difluoro-phenyl)-2-(R)-2-hydroxy-acetylamino]-pentanoic        acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.8 min, M+1=452.9    -   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide, LC-MS RT=2.2 min,        M+1=355.0    -   2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide, LC-MS RT=2.0 min,        M+1=341.0    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide, LC-MS RT=2.3 min,        M+1=410.9    -   2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide, LC-MS RT=2.2 min,        M+1=374.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-chloro-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.6 min, M+1=444.8    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.1 min, M+1=426.9    -   2-(5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-ylsulfanyl)-2-methyl-propionic        acid ethyl ester, LC-MS RT=2.8 min, M+1=500.8    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[(isopropyl-phenyl-carbamoyl)-methylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide,        LC-MS RT=2.8 min, M+1=561.8    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-fluoro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.9 min, M+1=494.8    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide,        1 H NMR(CDCl3/CD3OD)δ 8.74(d, 1 H), 7.37(d, 1H), 6.70(m,2H0,        6.57(m,1H),4.51 (m,1H), 3.43(s,2H), 1.71 (m, 1H), 1.69(m,1H),        1.26(m,2H), 0.87(t,3H) ppm.    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-allyl)-[1,3,4]thiadiazol-2-yl]-amide, LC-MS RT=2.6        min, M+1=409.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-propenyl)-[1,3,4]thiadiazol-2-yl]-amide, LC-MS        RT=2.6 min, M+1=409.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(2-benzyloxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=3.0 min, M+1=517.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[3-(toluene-4-sulfonylamino)-[1,2,4]thiadiazol-5-yl]-butyramide,        LC-MS RT=2.5 min, M+1=510.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (3-ethylsulfanyl-[1,2,4]thiadiazol-5-yl)-amide, LC-MS RT=2.7        min, M+1=415.2    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (3-methanesulfonyl-[1,2,4]thiadiazol-5-yl)-amide, LC-MS RT=2.3        min, M+1=433.2    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [3-(4-nitro-benzenesulfonylamino)-[1,2,4]thiadiazol-5-yl]-amide,        LC-MS RT=2.6 min, M+1=555.3    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (3-p-tolylamino-[1,2,4]thiadiazol-5-yl)-amide, LC-MS RT=2.4 min,        M+1=460.4    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (3-methyl-[1,2,4]thiadiazol-5-yl)-amide, LC-MS RT=2.1 min,        M+1=369.2

EXAMPLE 4 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-oxiranyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide

A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide (196 mg, 0.45mmol) and ˜60% pure m-chloroperbenzoic acid (109 mg, 0.45 mmol) inmethylene chloride was stirred for 4 hr. The mixture was quenched withwater, saturated Na₂S₂O₃ and extracted with methylene chloride. Theorganic layer was washed with brine, separated, dried, and concentratedto give 114 mg of crude material with a mixture of desired titlecompound and undesired N-oxide and recovered starting material. Thecrude material was purified by HPLC and the title compound was isolated,LC-MS, RT=2.3 min, M=1=453.5.

EXAMPLE 5 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide

A stream of ozone was generated and passed through a solution of2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide (631 mg,1.445 mmol) in 40 ml of methylene chloride until the mixture turned toblue solution or until the disappearance of starting material at −78° C.The mixture was stirred at −78° C. for 10 min, then the excess ozone wasreplaced with N₂ at −78° C. The mixture was quenched with excess ofdimethylsulfide and stirred at r.t. overnight. The mixture wasconcentrated to dryness, purified by Shimadzu HPLC to give the titlecompound as a yellow solid, RT=2.3 min, M+1=439.5.

3-(5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-yl)-3-methyl-butyricacid, was prepared as described above in which the ozonolysis providedsmall quantity of the title compound that was isolated as the titlecarboxylic acid, RT=2.1 min, M+1=455.5.

The following examples were prepared by the method analogous to thatdescribed in Example 5 starting with an appropriate olefin and ozone,followed by quenching with dimethylsulfide.

-   -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide, LC-MS        RT=2.1 min, M+1=425.5    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide,        APCI, M+1=411.1    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide,        LC-MS RT=2.2 min, M+1=424.9    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.4 min, M+1=454.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-acetyl-[1,3,4]thiadiazol-2-yl)-amide, LC-MS RT=2.3 min,        M+1=396.9

EXAMPLE 7 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-oxo-ethyl)-(1,3,4]thiadiazol-2-yl]-amide

A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid[5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (40 mg,0.93 mmol) and Dess-Martin periodinane(1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) (90 mg)in methylene chloride (3 ml) was stirred at rt for 3 hr. The mixture wasquenched with water, methylene chloride and filtered through celite. Thefiltrate was transferred to separatory funnel and the organic layer wasseparated, dried and concentrated to give 42 mg of crude material. Thecrude material was purified by silica gel column chromatography usingmethylene chloride to 1% methanol in methylene chloride as eluent togive 20 mg of the title compound as a tan glass solid. APCI M+1=425.2.

EXAMPLE 8 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-isopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide

A mixture of 2-(2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide (88 mg, 0.2mmol), isopropylamine (0.09 ml) in dichloroethane (1 ml) and methylenechloride (1 ml) was stirred at r.t. for 10 min, sodiumtriacetoxyborohydride (76 mg) was added and the resulting mixture wasstirred at r.t. overnight. The mixture was quenched with water, dilutedwith sodium hydroxide, and extracted with methylene chloride. Theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by silica gel columnchromatography using 3-5% methanol in methylene chloride, then 5%methanol/0.5% ammonium hydroxide in methylene chloride as eluent to givethe title compound as a free base form. The free base was treated with 4N HCl in doxane (0.1 ml) in methylene chloride (1 ml) and concentratedto dryness. The residue was triturated with hexane, pumped to dryness togive a white solid, LC-MS RT=1.8 min, M+1=481.9.

EXAMPLE 9 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-isopropylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide

A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide (63 mg, 0.148mmol), isopropylamine (0.2 ml) in dichloroethane (1 ml) and methylenechloride (1 ml) was stirred at r.t. for 10 min. Sodium cyanoborohydride(70 mg), acetic acid (0.1 ml), and sodium sulphate were added and theresulting mixture was stirred at 45-50° C. overnight. The mixture wasquenched with water, basified with saturated sodium carbonate, extractedwith methylene chloride. The organic layer was separated, dried overNa2SO₄, filtered and concentrated to dryness. The residue was purifiedby Shimadzu HPLC to give the title compound LC-MS RT=1.7 min, M+1=467.9.

The following Examples were prepared by the method analogous to thatdescribed in Examples 8 or 9 starting from an appropriate aldehyde orketone and an appropriate amine in an appropriate solvent or a mixtureof solvents selected from methylene chloride, dichloroethane, THF, orDMF in the presence of a reducing agent selected from NaBH₃CN orNaB(OAc)₃H with or without acetic acid.

-   -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1,1-dimethyl-3-(2,2,2-trifluoro-ethylamino)-propyl]-[1,3,4]thiadiazol-2-yl}-amide,        LC-MS, RT=1.6 min, M+1=522.6    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-ethylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide        HCl salt, LC-MS, RT=1.8 min, M+1=440.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-isopropylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide,        HCl salt, LC-MS, RT=1.6 min, M+1=453.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-isopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide,        LC-MS, RT=1.7 min, M+1=467.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-ethylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS, RT=1.9 min, M+1=467.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-dimethylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide        HCl salt, LC-MS, RT=1.6 min, M+1=468.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-propylamino-propyl)-[1,3,4]thiadiazol-2-yl]-amide,        HCl salt, LC-MS, RT=1.9 min, M+1=483.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[3-(2-hydroxy-ethylamino)-1,1-dimethyl-propyl]-[1,3,4]thiadiazol-2-yl}-amide,        HCl salt, LC-MS, RT=1.8 min, M+1=484.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-tert-butylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide        formic acid salt, LC-MS, RT=1.7 min, M+1=496.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-cyclopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide        formic acid salt, LC-MS, RT=1 .9min, M+1=480.2    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-[1,3,4]thiadiazol-2-yl]-amide        formic acid salt, LC-MS, RT=1.7 min, M+1=494.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1,1-dimethyl-3-morpholin-4-yl-propyl)-[1,3,4]thiadiazol-2-yl]-amide        formic acid salt, LC-MS, RT=1.5 min, M+1=510.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[3-(1-ethyl-propylamino)-1,1-dimethyl-propyl]-[1,3,4]thiadiazol-2-yl}-amide        formic acid salt, LC-MS, RT=1.8 min, M+1=510.0    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        [5-(3-cyclopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide        formic acid salt, LC-MS, RT=1.8 min, M+1=495.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        (5-{3-[formyl-(2,2,2-trifluoro-ethyl)-amino]-1,1-dimethyl-propyl}-[1,3,4]thiadiazol-2-yl)-amide,        LC-MS, RT=2.6 min, M+1=549.9    -   2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid        (5-{3-[formyl-(2,2,2-trifluoro-ethyl)-amino]-1,1-dimethyl-propyl}-[1,3,4]thiadiazol-2-yl)-amide,        LC-MS, RT=2.5 min, M+1=566.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(3-methyl-butylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide,        HCl salt, LC-MS, RT=1.9 min, M+1=468.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-butylamino-ethyl)-[1,3,4]thiadiazol-2-yl]-amide, HCl salt,        LC-MS, RT=1.9 min, M+1=454.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(3,3-dimethyl-butylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide        HCl salt, LC-MS, RT=2.2 min, M+1=482.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-cyclopropylamino-ethyl)-[1,3,4]thiadiazol-2-yl]-amide HCl        salt, LC-MS, RT=1.7 min, M+1=437.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(4-methyl-piperazin-1-yl)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide        formic acid salt, LC-MS, RT=1.7 min, M+1=481.0    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(4-chloro-benzylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide        formic acid salt, LC-MS, RT=2.3 min, M+1=521.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        {5-[1-(3-chloro-benzylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide        HCl salt, LC-MS, RT=2.2 min, M+1=521.9

EXAMPLE 102-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-hydroxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide

A mixture of2-[2-(3,5-difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl)]-butyramide(100 mg) and sodium borohydride (40 mg) in methanol was stirred at rtfor 5 min. The mixture was quenched with water, extracted with methylenechloride. The organic layer was separated, dried, filtered andconcentrated to give 90 mg of the tilte compound that was purified bysilica gel column chromatography using hexane/EtOAc=3/2 to EtOAc aseluent to give 80 mg of the title compound, LC-MS RT=2.1 min, M+1=426.9

The following examples were prepared by the method analogous to thatdescribed in Example 10 starting from an appropriate aldehyde or ketonewith excess of sodium borohydride in methanol.

-   -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(3-hydroxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide,        LC-MS RT=2.2 min, M+1=440.9    -   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid        [5-(1-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-amide LC-MS RT=1.9        min, M+1=398.9

EXAMPLE 11 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide

A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (41 mg),morpholine (25 mg), acetic acid (0.02 ml) in methylene chloride (1 ml)was stirred at room temperature for 1 hr, and sodiumtriacetoxyborohydride (42 mg) was added. The mixture was stirred at roomtemperature for at least two days. The mixture was quenched with dilutedNaOH and extracted with methylene chloride. The organic layer wasseparated, concentrated to dryness and the residue was purified bysilica gel column chromatography using 35% to 65% ethyl acetate inhexane as eluent to give the title compound. The title compound wasprepared as the corresponding HCl salt by adding HCl/doxane, followed byconcentration to give a solid. LC_MS retention time 1.7 min M+1=497.0,M−1=495.0.

EXAMPLE 12 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide

A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (22 mg),pyrrolidine (0.02 ml), acetic acid (0.01 ml) in methylene chloride (1ml) was stirred at room temperature for 1 hr, and sodiumtriacetoxyborohydride (28 mg) was added. The mixture was stirred at roomtemperature for at least two days. The mixture was quenched with dilutedNaOH and extracted with methylene chloride. The organic layer wasseparated, concentrated to dryness and the residue was purified bysilica gel column chromatography using 35% to 65% ethyl acetate inhexane as eluent to give the title compound. The title compound wasprepared as the corresponding HCl salt by adding HCl/doxane, followed byconcentration to give a solid. LC_MS retention time 2.0 min M+1=480.0.

Preparation A1-(5-tert-Butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butyl]-carbamic acidtert-butyl ester

A mixture of 2-tert-butoxycarbonylamino-pentanoic acid (5.432g, 25mmol.), 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine (3.925g, 25 mmol), HBOT(3.540g, 26.25 mmol), EDC HCl (5.73g, 30 mmol.) and triethylamine (14ml) in methylene chloride was stirred at room temperature until productformation or disappearance of starting material. The mixture wasquenched with water and extracted with methylene chloride. The organiclayer was separated, washed with dilute HCl, brine, dried over sodiumsulfate and the solvent was removed at reduced pressure to provide thetitle compound (9.2671 g), LC-MS M+1=357.2.

The following examples were prepared by the method analogous to that inPreparation A.

-   -   [1-(5-Methyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butyl]-carbamic        acid tert-butyl ester, M+1=315.4, 1H NMR(CDCl3) d 6.6(d,1H,NH),        4.4(m,1H), 2.7(s,3H), 1.2-1.9(m,4H), 1.3(s,9H), 0.95(t,3H) ppm.    -   [1-(5-Cyclopropyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butyl]-carbamic        acid tert-butyl ester, M+1=341.3    -   [1-(5-Ethyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butyl]-carbamic        acid tert-butyl ester, M+1=329.4, 1H NMR(CDCl3) d 7.0(s,1H,NH),        4.4(m,1H), 3.06(q,2H), 1.3-1.9(m,4H), 1.4(t,3H), 1.28(s,9H),        0.94(t,3H) ppm.    -   [1-(5-tert-Butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butyl]-carbamic        acid tert-butyl ester, LC-MS M+1=357.2    -   {1-[5-(1,1-Dimethyl-butyl)-[1,3,4]thiadiazol-2-ylcarbamoyl]-butyl}-carbamic        acid tert-butyl ester, LC-MS RT=2.9 min, M+1=385.5    -   {1-[5-(1,1-Dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-ylcarbamoyl]-butyl}-carbamic        acid tert-butyl ester, LC-MS RT=2.8 min, M+1=383.4    -   {1-[5-(1,1-Dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-ylcarbamoyl]-propyl}-carbamic        acid tert-butyl ester, LC-MS RT=2.6 min, M+1=369.4

Preparation B 2-Amino-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide

A mixture of[1-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butyl]-carbamic acidtert-butyl ester (8.9 g) in dioxane (60 ml) was treated with 4 N HCl in1,4-dioxane (20 ml). The mixture was stirred at rt overnight, thenconcentrated to dryness and pumped in vacuo to give the title compoundsas a white solid (7.0908g, 93%), APCI M+1=257.4

The following examples were prepared by the method analogous to thatdescribed in Preparation B.

-   -   2-Amino-pentanoic acid (5-methyl-[1,3,4]thiadiazol-2-yl)-amide,        M+1=215.3    -   2-Amino-pentanoic acid (5-ethyl-[1,3,4]thiadiazol-2-yl)-amide,        M+1=229.3    -   2-Amino-pentanoic acid        (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide, 1H NMR (CDCl3) d        4.15 (m,1H), 2.4(m,1H), 1.95(m,2H), 1.5(m,2H), 1.2-1.35(m,2H),        1.29(m,2H), 0.98(t,3H) ppm.    -   2-Amino-pentanoic acid        [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide, 1H NMR        (CDCl3) d 4.14 (m,1H), 1.95(m,2H), 1.7(m,2H), 1.5(m,2H),        1.45(s,6H), 1.25(m,2H), 1.01(t,3H), 0.89(t,3H) ppm.

Based on a reading of the present description and claims, certainmodifications to the compounds, compositions and methods describedherein will be apparent to one of ordinary skill in the art. The claimsappended hereto are intended to encompass these modifications.

1. A compound of the formula

wherein the ring containing X, Y, U is an aromatic ring in which one ofthe X, Y, U is a S and the other two of the X, Y, U are N as shown belowI-A to I-C:

wherein Z is selected from —C(═O)CHR¹R², —C(═S)CHR¹R², —(C═NR⁸)CHR¹R²,—C(═O)C(═O)R¹ and —S(O)₂—R¹; R¹ is selected from —C₁-C₂₀ alkyl, —C₂-C₂₀alkenyl, —C₂-C₂₀ alkynyl, —C₁-C₂₀ alkoxy, —C₂-C₂₀ alkenoxy, —C₂-C₂₀alkynoxy, —C₃-C₂₀ cycloalkyl, —C₄-C₂₀ cycloalkenyl, (C₁₀-C₂₀)bi- ortricycloalkyl, (C₁₀-C₂₀)bi- or tricycloalkenyl, (4-20 membered)heterocycloalkyl, —C₆-C₂₀ aryl and (5-20 membered) heteroaryl; whereinR¹ is optionally independently substituted with from one to six fluorineatoms or with from one to three substituents independently selected fromthe group R^(1a); R^(1a) is in each instance independently selected from—OH, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —C₁-C₆ alkoxy,—C₂-C₆ alkenoxy, —C₂-C₆ alkynoxy, —CF₃, —OCF₃, —Cl, —Br, —I, —CN, —NO₂,—NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —SO₂—NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)—R¹¹,—C(═O)OR¹², —C₃-C₁₅ cycloalkyl, —C₄-C₁₅ cycloalkenyl, —(C₅-C₁₁)bi- ortricycloalkyl, —(C₇-C₁₁)bi- or tricycloalkenyl, -(4-20 membered)heterocycloalkyl, —C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, —C₆-C₁₅aryloxy and -(5-15 membered) heteroaryloxy, wherein said cycloalkyl,cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl,heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy are eachoptionally independently substituted with from one to three substituentsindependently selected from the group R^(1b); R^(1b) is in each instanceindependently selected from —OH, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆ alkynoxy, —C₁-C₆hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,—C(═O)R¹¹, —S(O)_(n)—R¹¹, —C₆-C₁₅ aryloxy and -(5-15 membered)heteroaryloxy, wherein said alkyl, alkenyl and alkynyl are eachoptionally independently substituted with from one to six fluorine atomsor with from one to two substituents independently selected from —C₁-C₄alkoxy, or with a hydroxy group; R⁹ and R¹⁰ are in each instance eachindependently selected from —H, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂alkynyl, —CF₃, —C(═O)R¹¹, —S(O)_(n)—R¹¹, —C(═O)OR¹², —C(═O)NR¹¹R¹²,—SO₂—NR¹¹R¹², —(C_(zero)-C₄ alkylene)-(C₃-C₂₀ cycloalkyl), —(C_(zero)-C₄alkylene)-(C₄-C₈ cycloalkenyl), —(C_(zero)-C₄ alkylene)-((C₅-C₁₁)bi- ortricycloalkyl), —(C_(zero)-C₄ alkylene)-((C₇-C₁₁)bi- ortricycloalkenyl), —(C_(zero)-C₄ alkylene)-((5-10 membered)heterocycloalkyl), (C_(zero)-C₄ alkylene)-(C6-C₁₀ aryl) and—(C_(zero)-C₄ alkylene)-((5-10 membered) heteroaryl), wherein said aryl,heteroaryl, alkyl, alkenyl and alkynyl are each optionally independentlysubstituted with from one to six fluorine atoms or with from one to twosubstitutents independently selected from —C₁-C₄ alkoxy, or with ahydroxy group, and wherein said cycloalkyl, cycloalkenyl, bi-ortricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl andheteroaryl are each optionally independently substituted with from oneto three substituents independently selected from —OH, —C₁-C₁₂ alkyl,—C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆alkynoxy, —C₁-C₆ hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —NH₂,—C(═O)NH₂, —SO₂—NR⁹R¹⁰, —C(═O)H and —C(═O)OH, wherein said alkyl,alkenyl and alkynyl substituents are each optionally independentlyfurther substituted with from one to six fluorine atoms or with from oneto two substituents independently selected from —C₁-C₄ alkoxy, or with ahydroxy group; or NR⁹R¹⁰ may in each instance independently optionallyform a heterocycloalkyl moiety of from four to ten ring members, saidheterocycloalkyl moiety optionally containing one to two furtherheteroatoms independently selected from N, O and S, and optionallycontaining from one to three double bonds, wherein the carbon atoms ofthe heterocycloalkyl moiety of NR⁹R¹⁰ are optionally independentlysubstituted with from one to three substituents independently selectedfrom —OH, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl, —C₁-C₆alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆ alkynoxy, —F, —Cl, —Br, —I, —CF₃, —NH₂,—C(═O)NH₂, —SO₂—NH₂, —C(═O)R¹¹, —S(O)_(n)—R¹¹, (C_(zero)-C₄alkylene)-(C₆-C₁₀ aryl), (C_(zero)-C₄ alkylene)-((5-10 memberedheteroaryl), (C_(zero)-C₄ alkylene)-(C₆-C₁₀ cycloalkyl) and (C_(zero)-C₄alkylene)-((5-10 membered) heterocycloakyl, and wherein the (C_(zero)-C₄alkylene)-((5-10 membered) heterocycloalkyl) substituent and thenitrogen atoms of said heterocycloalkyl moiety of NR⁹R¹⁰ are eachoptionally independently substituted with one substituent independentlyselected from —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₂-C₁₂ alkynyl,—C(═O)NH₂, —SO₂—NH₂, C(═O)R¹¹, —S(O)_(n)—R¹¹, (C_(zero)-C₄alkylene)-(C₆-C₁₀ aryl), (C_(zero)-C₄ alkylene)-((5-10 membered)heteroaryl), (C_(zero)-C₄ alkylene)-(C₆-C₁₀ cycloalkyl) and (C_(zero)-C₄alkylene)-((5-10 membered) heterocycloalkyl), and wherein said alkyl,alkenyl and alkynyl substituents are each optionally independentlyfurther substituted with from one to six fluorine atoms, or with fromone to two substituents independently selected from —C₁-C₄ alkoxy, orwith a hydroxy group; R¹¹ and R¹² are in each instance eachindependently selected from —C₁-C₁₅ alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —(C_(zero)-C₄ alkylene)-(C₃-C₁₅ cycloalkyl), —(C_(zero)-C₄alkylene) cycloalkenyl), —(C_(zero)-C₄ alkylene)-((C₅-C₁₁)bi- ortricycloalkyl), —(C_(zero)-C₄ alkylene)-((C₇-C₁₁)bi- ortricycloalkenyl), —(C_(zero)-C₄ alkylene)-(C₆-C₁₅ aryl), —(C_(zero)-C₄alkylene)-((5-15 membered) heterocycloalkyl) and —(C_(zero)-C₄alkylene)-((5-15 membered) heteroaryl); wherein R¹¹ and R¹² are eachoptionally independently substituted with from one to three substituentsindependently selected from the group R^(1b); R² is selected from —H,—OH, —NH₂, —CH₂OH, —OC(═O)CH₃, —C(CH₃)₂OH, —C(CH₃)(CH₂CH₃)(OH),—C(OH)(C_(zero)-C₄ alkyl)(C_(zero)-C₄ alkyl), —OC(═O)R⁴ and —OC(═O)OR⁴,wherein said —OC(═O)R⁴ and —OC(═O)OR⁴ may optionally be a prodrug of thecorresponding OH of R²; R³ is selected from —C₁-C₆ alkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl and —(C_(zero)-C₄ alkylene)-(C₃-C₆ cycloalkyl),wherein when R³ is alkyl, alkenyl or alkynyl, R³ is optionallyindependently substituted with a substituent independently selected from—C₁-C₄ alkoxy, —OH, —F and —S(C₁-C₄ alkyl); R⁴ is selected from —C₁-C₄alkyl, —CH(OH)(C₁-C₄ alkyl), —CH(OH)(C₅-C₆ aryl), —CH(OH)((5-6 membered)heteroaryl), —CH(OH)(C₅-C₆ cycloalkyl), —CH(OH)((5-6 membered)heterocycloalkyl); R⁵ is selected from —H, —C₁-C₄ alkyl, —C₂-C₄ alkenyl,—C₂-C₄ alkynyl, —C(═O)(C₁-C₄ alkyl), —C₆-C₁₀aryl, -(5-20 membered)heteroaryl, —SO₂—(C₆-C₁₀ aryl), —SO₂-((5-20 membered) heteroaryl),—SO₂—CH₂—(C₆-C₂₀ aryl) and —SO₂-CH₂-((5-20 membered) heteroaryl); R⁷ isselected from —H, —C₁-C₂₀ alkyl, —C₂-C₂₀ alkenyl, —C₂-C₂₀ alkynyl,—C₁-C₂₀ alkoxy, —C₂-C₂₀ alkenoxy, —C₂-C₂₀ alkynoxy, —F, —Cl, —Br, —I,—CN, —NO₂, —OH, —CF₃, —NR⁹R¹⁰, —(C₁-C₁₁ alkyene)-NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,—C(═O)R¹¹, —CHO, —S(O)_(n)—R¹¹, —C(═O)OR¹², —(C_(zero)-C₄alkylene)-(C₃-C₂₀ cycloalkyl), —(C_(zero)-C₄ alkylene)-(C₄-C₂₀cycloalkenyl), —(C_(zero)-C₄ alkylene)-((C₁₀-C₂₀)bi- or tricycloalkyl),—(C_(zero)-C₄ alkylene)-((C₁₀-C₂₀)bi- or tricycloalkenyl), —(C_(zero)-C₄alkylene)-((3-20 membered) heterocycloalkyl), —(C_(zero)-C₄alkylene)-(C₆-C₁₅ aryl), —(C_(zero)-C₁₁ alkylene)-(C(═O)R¹¹, —(C₁-C₁₁alkylene)-(COOH), —(C_(zero)-C₁₁ alkylene)-CHO, —SO₂NR⁹R¹⁰,—S—(C₁-C₂₀alkylene)(C═O)OR⁸, —S—(C₁-C₂₀alkylene)-O—(C₁-C₁₁alkyl),—S—(C₁-C₂₀alkylene)-O—(C₅-C₁₁aryl), —SO₂NR⁹R¹⁰,—S—(C₁-C₂₀alkylene)-NR⁹R¹⁰, —(C₁-C₁₁alkylene)-O—(C_(zero)-C₄alkylene)-O—(C₆-C₁₁aryl), and —(C_(zero)-C₄alkylene)-((5-15 membered) heteroaryl), wherein said heterocycloalkyloptionally contains from one to four double or triple bonds; wherein R⁷is optionally substituted with from one to six fluorine atoms or withfrom one to three substituents independently selected from the groupR^(1a); R⁸ is selected from —H and —C₁-C₆ alkyl; or, when Z is—C(═NR⁸)CHR¹R², R⁸ and R¹ may together with the nitrogen and carbonatoms to which they are respectively attached optionally form a five tofourteen membered heteroaryl ring or a five to eight memberedheterocycloalkyl ring, wherein said heteroaryl or heterocycloalkyl ringoptionally contains from one to two further heteroatoms selected from N,O and S, and wherein said heterocycloalkyl ring optionally contains fromone to three double bonds, and wherein said heteroaryl orheterocycloalkyl ring is optionally substituted with from one to threesubstituents independently selected from the group R^(1b); n is 0, 1, 2or the pharmaceutically acceptable salts of such compounds.
 2. Acompound according to claim 1, wherein Z is —C(═O)CHR¹R², R² is —H, —OH,or OC(═O)CH₃.
 3. A compound according to claim 1, wherein Z is—C(═O)C(═O)R¹.
 4. A compound according to claim 1, wherein Z is —SO₂R¹.5. A compound according to claim 1, wherein R¹ is selected from —C₁-C₂₀alkyl, —C₂-C₂₀ alkenyl, —C₂-C₂₀ alkynyl, —C₃-C₂₀ cycloalkyl, (4-20membered) heterocycloalkyl, —C₆-C₂₀ aryl and (5-20 membered) heteroaryl.6. A compound according to claim 5, wherein R¹ is selected from —C₁-C₁₀alkyl, —C₂-C₁₀ alkenyl, —C₃-C₁₀ cycloalkyl, phenyl, thienyl and pyridyl,wherein R¹ is optionally independently substituted with from one to twosubstituents independently selected from —C₁-C₄ alkyl, —OCF₃, —CF₃,—C₁-C₄ alkoxy, —F, —Cl, —Br, phenyl and phenoxy, wherein R¹ optionallycontains one or two double or triple bonds.
 7. A compound according toclaim 6, wherein R¹ is —C₃-C₇ cycloalkyl, e.g., [2.2.1 ]-heptanyl.
 8. Acompound according to claim 6, wherein R¹ is selected from phenyl andpyridyl, wherein R¹ is optionally independently substituted with fromone to two substitutents independently selected from —F, —Cl —OCF₃, and—CF₃.
 9. A compound according to claim 1, wherein R² is selected from—H, —OH, and —OC(═O)CH₃.
 10. A compound according to claim 9, wherein R²is selected from —H and —OH.
 11. A compound according to claim 9,wherein 9 R² is —H or —OH, as shown in formula I-A.
 12. A compoundaccording to claim 1, wherein the compound of Formula I has thefollowing structure:


13. A compound according to claim 1, wherein R³ is selected from —C₁-C₄alkyl, allyl, and —CH₂CH₂SCH₃.
 14. A compound according to claim 1,wherein R⁵ is H.
 15. A compound according to claim 1, wherein R⁷ isselected from —H, —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₁-C₂₀ alkoxy, —F,—Cl, —Br, —I, —CN, —NO₂, —C₃-C₁₅ cycloalkyl, -(3-5 membered)heterocycloalkyl, —C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, —CHO,—C(═O)(C₁-C₁₅ alkyl), —C(═O)((5-15 membered) heterocycloalkyl),—C(═O)((5-15 membered) heteroaryl), —C(═O)O(C₁-C₈ alkyl), —C(═O)N(C₁-C₁₀alkyl)(C₁-C₁₀ alkyl), —S(O)_(n)-alkyl, —S(O)_(n)-cycloalkyl,—S(O)_(n)-aryl, —S(O)_(n)-(5 to 10 membered) heteroaryl, and whereinsaid alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are eachoptionally independently substituted with from one to three substituentsindependently selected from —F, —Cl, —Br, —O, —OH, —C₁-C₆ alkoxy, —C₂-C₆alkenoxy, —C₂-C₆ alkynoxy, —NR⁹R¹⁰, —(C₁-C₁₁ alkyene)-NR⁹R¹⁰, —C(═O)R¹¹,—S(O)_(n)R¹¹, —C(═O)OR¹², —C(═O)NR⁹R¹⁰, —S(O)_(n)NR⁹R¹⁰—C₃-C₁₅cycloalkyl, -(4-15 membered) heterocycloalkyl, —C₆-C₁₅ aryl, -(5-15membered) heteroaryl, -(4-15 membered) heterocycloalkoxy, —C₆-C₁₂aryloxy and -(6-12 membered) heteroaryloxy.
 16. A compound according toclaim 15, wherein R⁷ is selected from —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl,—C₃-C₁₅ cycloalkyl and -(4-15 membered) heterocycloalkyl, and whereinsaid alkyl, alkenyl, cycloalkyl and heterocycloalkyl are each optionallyindependently substituted with from one to three substitutentsindependently selected from —OH, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆alkynoxy and —NR⁹R¹⁰.
 17. A compound according to claim 16, wherein R⁷is selected from —C₁-C₁₂ alkyl, —C₂-C₁₂ alkenyl, —C₃-C₁₅ cycloalkyl and-(4-15 membered) heterocycloalkyl, and wherein said alkyl, alkenyl,cycloalkyl and heterocycloalkyl are each optionally independentlysubstituted with from one to three substitutents independently selectedfrom —OH, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆ alkynoxy.
 18. Acompound according to claim 17, wherein R⁷ is selected from —C₁-C₁₂alkyl, —C₂-C₁₂ alkenyl and —C₃-C₁₅cycloalkyl, and wherein said alkyl,alkenyl and cycloalkyl are each optionally independently substitutedwith from one to three substitutents NR⁹R¹⁰.
 19. A compound according toclaim 1, wherein R⁷ is -(4-15 membered) heterocycloalkyl, and whereinsaid heterocycloalkyl is optionally substituted with from one to threesubstitutents independently selected from —OH, —C₁-C₆ alkyl, —C₂-C6alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkoxy, —C₂-C₆ alkenoxy, —C₂-C₆alkynoxy, —(C₆-C₁₀ aryl) and -(5-15 membered) heteroaryl.
 20. A compoundaccording to claim 1 selected from the group consisting of:2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-phenyl-[1,3,4]thiadiazol-2-yl )-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(4-methoxy-phenyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3,4-dimethyl-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-adamantan-1-yl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(4-chloro-benzyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-(2-phenyl-propylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-trifluoromethyl-benzylsulfanyl)-thiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-methoxy-benzylsulfanyl)-thiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(2-fluoro-benzylsulfanyl)-thiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-propylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[2-(3-trifluoromethyl-phenoxy)-ethylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3,4-dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-dipropylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-benzylsulfanyl-[1,3,4]thiadiazol-2-yl )-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(2,4-dichloro-phenoxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(4-phenoxy-butylsulfanyl)-thiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[2-(4-bromo-phenoxy)-ethylsulfanyl]-thiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-diethylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-ethylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-phenethylsulfanyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl )-amide;2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-2-(S)-hydroxy-acetylamino]-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid(5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid(5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)-pentanoic acid(5-ethyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-methyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-(S)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid(5-methyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-(R)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid(5-methyl-[1,3,4]thiadiazol-2-yl)-amide; Hydroxy-phenyl-acetic acid[1-(5-methyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-butylcarbamoyl]-phenyl-methylester; 2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid(5-methyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid(5-methyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic acid(5-methyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-2-(R)-2-hydroxy-acetylamino]-pentanoic acid(5-methyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-formyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(2,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(2,4,4-trimethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-(S)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-(R)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-(S)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-(R)-2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-(S)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid[5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-(R)-2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid[5-(1-ethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-(S)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid[5-(1-ethyl-pentyl)-(1,3,4]thiadiazol-2-yl]-amide;2-(2-(R)-Hydroxy-2-phenyl-acetylamino)-pentanoic acid[5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-isopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid[5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid[5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(S)-2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid[5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(R)-2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid[5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(5-Bromo-pyridin-3-yl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3-Trifluoromethoxy-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;3-(5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-3-yl]-methyl-butyricacid; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-oxiranyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-3-oxy-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1,1-dimethyl-3-(2,2,2-trifluoro-ethylamino)-propyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-methyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-methyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-butyl)-1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-isopropylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3,3-dimethoxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-ethylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-isopropylamino-1-methyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-hydroxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(3-isopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-ethylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-2-(R)-2-hydroxy-acetylamino]-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-2-(S)-2-hydroxy-acetylamino]-pentanoic acid[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-dimethylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-3-propylamino-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[3-(2-hydroxy-ethylamino)-1,1-dimethyl-propyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-tert-butylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-cyclopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-3-morpholin-4-yl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[3-(1-ethyl-propylamino)-1,1-dimethyl-propyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid[5-(3-cyclopropylamino-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-hydroxy-1,1-dimethyl-propyl)-[1,3,4]thiadiazol-2-yl]-amide-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoicacid(5-{3-[formyl-(2,2,2-trifluoro-ethyl)-amino]-1,1-dimethyl-propyl}-[1,3,4]thiadiazol-2-yl)-amide2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid(5-{3-[formyl-(2,2,2-trifluoro-ethyl)-amino]-1,1-dimethyl-propyl}-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid[5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Hydroxy-3-methyl-butyrylamino)-pentanoic acid(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-pentanoic acid(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;2-(2-Hydroxy-2-phenyl-acetylamino)-pentanoic acid(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(2-chloro-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-(5-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-ylsulfanyl)-2-methyl-propionicacid ethyl ester; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[(isopropyl-phenyl-carbamoyl)-methylsulfanyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-fluoro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-methyl-allyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-methyl-propenyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-acetyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(3-methyl-butylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-butylamino-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(3,3-dimethyl-butylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-cyclopropylamino-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(4-methyl-piperazin-1-yl)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(4-chloro-benzylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(3-chloro-benzylamino)-ethyl]-[1,3,4]thiadiazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(2-benzyloxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-ethylsulfanyl-[1,3,4]thiadiazol-2-yl)-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(2-dimethylamino-ethylsulfanyl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-ethoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-dimethylamino-[1,3,4]thiadiazol-2-yl)-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isobutyl-[1,3,4]thiadiazol-2-yl)-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-phenyl-[1,3,4]thiadiazol-2-yl)-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-butyramide;N-(5-Benzyl-[1,3,4]thiadiazol-2-yl)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-phenoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;N-[5-(3-Chloro-phenyl)-[1,3,4]thiadiazol-2-yl]-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;N-(5-Cyclobutyl-[1,3,4]thiadiazol-2-yl)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]thiadiazol-2-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-methoxymethyl-[1,3,4]thiadiazol-2-yl)-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-(5-isopropylsulfanyl-[1,3,4]thiadiazol-2-yl)-butyramide;2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-cyclohexyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-methylsulfamoyl-[1,3,4]thiadiazol-2-yl)-amide;2-(5-{2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoylamino}-[1,3,4]thiadiazol-2-ylsulfanyl)-propionicacid ethyl ester; 2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-phenethyl-[1,3,4]thiadiazol-2-yl)-amide;2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid[5-(1-phenoxy-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[3-(toluene-4-sulfonylamino)-[1,2,4]thiadiazol-5-yl]-butyramide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(3-ethylsulfanyl-[1,2,4]thiadiazol-5-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(3-methanesulfonyl-[1,2,4]thiadiazol-5-yl)-amide; and2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[3-(4-nitro-benzenesulfonylamino)-[1,2,4]thiadiazol-5-yl]-amide.
 21. Apharmaceutical composition for inhibiting Aβ-peptide production in amammal, comprising an amount of the compound according to claim 1 thatis effective in inhibiting Aβ-production, and a pharmaceuticallyacceptable carrier.
 22. A pharmaceutical composition for treating adisease or condition selected from the group consisting of Alzheimer'sdisease, hereditary cerebral hemorrhage with amyloidosis, cerebralamyloid angiopathy, a prion-mediated disease, inclusion body myositis,stroke, multiple sclerosis and Down's Syndrome in a mammal, comprisingan amount of the compound according to claim 1 that is effective ininhibiting Aβ-peptide production, and a pharmaceutically acceptablecarrier.
 23. A pharmaceutical composition for treating a disease or acondition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis and Down's Syndrome in a mammal, comprising an amountof the compound according to claim 1 that is effective in treating suchdisease or condition, and a pharmaceutically acceptable carrier.
 24. Amethod of inhibiting Aβ-peptide production in a mammal, comprisingadministering to said mammal an amount of the compound according toclaim 1 that is effective in inhibiting Aβ-production.
 25. A method oftreating a disease or condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis and Down's Syndrome in a mammal,comprising administering to said mammal an amount of the compoundaccording to claim 1 that is effective in inhibiting Aβ-production. 26.A method of treating a disease or condition selected from the groupconsisting of Alzheimer's disease, hereditary cerebral hemorrhage withamyloidosis, cerebral amyloid angiopathy, a prion-mediated disease,inclusion body myositis, stroke, multiple sclerosis and Down's Syndromein a mammal, comprising administering to said mammal an amount of thecompound according to claim 1 that is effective in treating suchcondition.
 27. A pharmaceutical composition for treating a disease orcondition associated with Aβ-peptide production in a mammal, comprising(a) the compound according to claim 1; (b) a memory enhancement agent,antidepressant, anxiolytic, antipsychotic agent, sleep disorder agent,anti-inflammatory agent, anti-oxidant agent, cholesterol modulatingagent or anti-hypertensive agent; and (c) a pharmaceutically acceptablecarrier; wherein the active agents “a” and “b” above are present inamounts that render the composition effective in treating such diseaseor condition.
 28. A pharmaceutical composition for treating a disease orcondition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis and Down's Syndrome, in a mammal, comprising (a) thecompound according to claim 1; (b) a memory enhancement agent,antidepressant, anxiolytic, antipsychotic agent, sleep disorder agent,anti-inflammatory agent, anti-oxidant agent, cholesterol modulatingagent or anti-hypertensive agent; and (c) a pharmaceutically acceptablecarrier; wherein the active agents “a” and “b” above are present inamounts that render the composition effective in treating such diseaseor condition.
 29. A method of treating a disease or condition associatedwith Aβ-peptide production in a mammal, comprising administering to saidmammal (a) the compound according to claim 1; and (b) a memoryenhancement agent, antidepressant, anxiolytic, antipsychotic agent,sleep disorder agent, anti-inflammatory agent, anti-oxidant agent,cholesterol modulating agent or anti-hypertensive agent; wherein theactive agents “a” and “b” above are present in amounts that render thecomposition effective in treating such disease or condition.
 30. Amethod of treating a disease or condition selected from the groupconsisting of Alzheimer's disease, hereditary cerebral hemorrhage withamyloidosis, cerebral amyloid angiopathy, a prion-mediated disease,inclusion body myositis, stroke, multiple sclerosis and Down's Syndrome,in a mammal, comprising administering to said mammal (a) the compoundaccording to claim 1; and (b) a memory enhancement agent,antidepressant, anxiolytic, antipsychotic agent, sleep disorder agent,anti-inflammatory agent, anti-oxidant agent, cholesterol modulatingagent or anti-hypertensive agent; wherein the active agents “a” and “b”above are present in amounts that render the composition effective intreating such disease or condition.
 31. A method of treating Alzheimer'sdisease in a mammal, comprising administering to said mammal (a) thecompound according to claim 1; and (b) a memory enhancement agent,antidepressant, anxiolytic, antipsychotic agent, sleep disorder agent,anti-inflammatory agent, anti-oxidant agent, cholesterol modulatingagent or anti-hypertensive agent; wherein the active agents “a” and “b”above are present in amounts that render the composition effective intreating such disease or condition.